乌鸦传媒

ORLANDO -- Heart failure patients with preserved ejection fraction not only do not improve their exercise tolerance if treated with isosorbide mononitrate, they do worse.

Nitrate treatment did not improve levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) or increase distance on a 6-minute walk, according to , of the Mayo Clinic, who reported the findings from the Nitrate's Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) as a late-breaking clinical trial at the American Heart Association meeting here.

At every tested nitrate dose, patients had lower levels of activity than patients taking placebo, Redfield said.

"With increasing nitrate doses activity decreased significantly," she said. Also more patients taking nitrates had worsening heart failure and worsening syncope.

Redfield said it was difficult to estimate the exact level of nitrate use in HFpEF patients, but published studies suggest that the drugs are used in 15% to 50% of patients. "My assessment, however, is that this study provides a very strong signal that nitrates have no benefit and may have promote adverse events in patients," she said.

, medical director of the Penn Heart and Vascular Center in Philadelphia, agreed that it was very difficult to assess nitrate use, and she suggested that when it was used, it reflected the desperation of clinicians seeking "something that works." But the findings from NEAT would clarify the issue for herself and others treating HFpEF. Jessup, who is a former AHA president, moderated a press briefing where the NEAT results were discussed.

Redfield added that inorganic nitrite or nitrate might have been a better choice for the study drug because either could increase "nitric oxide bioavailability during exercise."

The NEAT-HFpEF results were simultaneously published in the.

, of Feinberg School of Medicine at Northwestern University, told 乌鸦传媒 that the results should "put an end to investigating this drug in these patients."

But Bonow, who is a former president of the AHA and editor of , said it was worthwhile to study nitrates in HFpEF "because we are still searching for a drug that works in these patients and we are still also looking at some of the mechanisms involved."

Redfield noted that "exercise intolerance is a cardinal feature of HFpEF." Among patients with reduced ejection fraction, nitrates have been shown to improve exercise tolerance, thus it has become common practice to use nitrates in patients with smaller hearts who have heart failure, but there was no evidence to support that practice.

The study recruited 110 patients with HFpEF and randomly assigned them to a dose escalating regimen of isosorbide mononitrate (30 mg, 60 mg, 120 mg/daily) or placebo. After 6 weeks, the patients in the active arm were crossed to the placebo group and the placebo patients to the nitrate group for 6 weeks.

The primary endpoint was assessed physical activity units averaged over 14 days between the nitrate and placebo phases. Secondary endpoints included daily accelerometer units on all three nitrate doses, quality of life score, 6-minute walk distance, and NT-proBNP level.

The average age of patients was 69 and roughly half had New York Heart Association class II/III heart failure. Most patients were white and were obese, Redfield said.

All patients were receiving standard therapy with a variety of drugs including loop diuretics, thiazides, ACE inhibitors or ARBs, beta-blockers, antiplatelet or anticoagulants, aldosterone agonists, calcium channel blockers, and lipid-lowering agents.

Redfield said the trial results may have been limited by the rapid dose escalation regimen. HFpEF patients are especially sensitive to changes in hemodynamics, thus a a more gradual dose change might have been more effective.

"These data do not support use of long acting nitrates for symptom relief in HFpEF," she said. But she added that the use of accelerometer measurement with patient worn devices provided "unique information about the impact of therapies on patients daily functional status."

Comment