No Exercise Capacity Boost From Inhaled Nitrite in Preserved-EF Heart Failure: INDIE-HFpEF

March 19, 2018

ORLANDO — Inhaled doses of inorganic nitrite for 4 weeks had no apparent effects on peak exercise capacity or symptoms in patients with heart failure and preserved ejection fraction (HFpEF) in a 12-week randomized, crossover study.

But researchers say they aren't giving up on the strategy, given few pharmacologic options for treating HFpEF and a strong sense that some form of inorganic nitrate or nitrite administration may help fill that role. There's a sizable base of evidence that they promote favorable nitric oxide (NO) effects on vascular function and other physiologic systems involved in hypertension and heart failure.

Also, there were biomarker signs in the study, called Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction (INDIE-HFpEF), that inhalation of the short-acting nitrite preparation transiently boosted NO levels, and a subgroup analysis hinted at a possible benefit in some subgroups.

Other Forms of Nitrite Delivery?

"Alternative regimens which provide more consistent, higher levels of nitric oxide throughout the course of the day might achieve different results," proposed Barry Borlaug, MD, Mayo Clinic, Rochester, Minnesota, when presenting the study here at the American College of Cardiology (ACC) 2018 Annual Scientific Sessions.

Studies using oral forms of nitrate as well as nitrites, to which oral bacteria convert nitrates before they are ingested, have shown "very promising results," Borlaug said, "with improvements in exercise capacity." Beetroot juice, which contains high levels of nitrate, has been widely studied this way.

"So there's a still good deal of hope that maybe that will work better," he said, and that those oral forms might lead to "longer-lived nitrate and nitrite levels that might be more sustained and effective."

The studies using beetroot juice and other oral nitrate sources have provided "really compelling data" that they might enhance exercise capacity and help in other ways in patients with heart failure, James L Januzzi Jr, MD, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology.

That nitrite inhalation didn't seem to work in INDIE-HFpEF is probably related to its small size, the brief exposures to the agent, the short-acting nature of the agent, and the lack of exercise training as part of the intervention, said Januzzi, who wasn't connected with the study.

Hint of Subgroup Effect

The trial's 105 patients with NYHA class 2 to 4 heart failure, an LVEF of 50% or greater, and elevated natriuretic peptides were assigned double-blind to self-administer 46 to 80 mg aerosolized nitrite or placebo three times daily for 4 weeks while wearing an accelerometer. They crossed to the other treatment assignment after a 2-week washout period.

No significant differences were seen on vs off nitrite therapy for the primary endpoint of change in peak VO2 after 4 weeks. Nor were there differences in daily activity levels, NYHA class, quality-of-life measures, systolic blood pressure, echocardiographic left ventricular filling pressures, or natriuretic peptide levels. All patients tolerated the treatments, and no safety issues were observed.

The only subgroups to show signs of a positive effect from nitrite intake were those who entered the study with higher levels of brain-type natriuretic peptide (BNP) and the nearly half of the cohort who were in atrial fibrillation (AF), Borlaug told theheart.org | Medscape Cardiology.

"The patients with atrial fibrillation tended to do better with the nitrite, whereas the people without atrial fibrillation tended not to," Borlaug said. Both AF and elevated natriuretic peptides "are indicators of a more advanced, sicker population."

The signal of benefit in patients with those two features can only be hypothesis-generating in a study such as this, observed Januzzi in an interview. "But I actually think those findings are real," he added.

Because AF is usually associated with elevated natriuretic peptides, Januzzi said, "it's probable that the patients with high BNP were also the patients with atrial fibrillation, and vice versa. So, we're talking about a phenotype. We're talking about a descriptive group of patients that may have a different type of HFpEF that might be more treatment-responsive."

It is increasingly clear that HFpEF is a heterogeneous group of syndromes, "so individualizing care is really going to be important," he said.  "We might ultimately be able to find patients in whom one therapy might be beneficial but might not be beneficial at all in another population within HFpEF."

Borlaug discloses receiving honoraria or fees for consulting from Actelion, Amgen, Arteriomedix, Merck, and MyoKardia and research grants from AstraZeneca, Corvia, GlaxoSmithKline, Medtronic, and Mesoblast. Januzzi discloses receiving honoraria or fees for consulting from Abbott, Critical Diagnostics, Phillips, and Roche Diagnostics; serving on a data safety monitoring board for AbbVie, Amgen, Boehringer Ingelheim, Janssen Pharmaceuticals, and Siemens; and receiving research grants from Cleveland Heart Labs, Novartis, Prevencio, and Singulex.

American College of Cardiology (ACC) 2018 Annual Scientific Session. Presentation 405-10. Presented March 11, 2018.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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