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ORLANDO -- An inhaled inorganic nitrite improved neither exercise capacity nor general clinical status for patients with heart failure with preserved ejection fraction (HFpEF), according to the INDIE-HFpEF trial.

Delivery of the compound by nebulizer did not improve peak exercise capacity on cardiopulmonary exercise testing, as it left patients with the same 14 ml/min/kg VO₂ as their peers randomized to placebo (P=0.27), Barry Borlaug, MD, of the Mayo Clinic in Rochester, Minnesota, reported at the annual meeting here.

The nitrite did not increase daily activity or patient-reported quality of life. It also failed to improve heart failure symptom severity and cardiac congestion. But nor was there an uptick in severe adverse events with the inhaled compound, the presenter said during the late-breaking trial session.

"These data do not support use of inhaled, nebulized inorganic nitrite for symptom relief in patients with HFpEF," he concluded. The hope was that inorganic nitrite, which restores nitric oxide, might improve exercise capacity and clinical status in patients with HFpEF given evidence suggesting that impaired nitric oxide signalling may drive heart failure.

"HFpEF remains an enormous unmet public health problem. Further study is required to determine the potential efficacy of other nitric oxide-providing therapies in HFpEF," Borlaug urged.

Previously, researchers had found that organic nitrate supplementation was poorly tolerated and in fact reduced patient activity levels.

Session panelist Lee Goldberg, MD, MPH, of the Hospital of the University of Pennsylvania in Philadelphia, said he was left wondering after the INDIE-HFpEF presentation if the inhaled nitrite was actually being absorbed and whether researchers have been targeting the wrong pathway in HFpEF all along.

The trial "certainly doesn't support the hypothesis" that it's nitric oxide that's driving HFpEF, the presenter responded. Yet there are several ways to target it upstream or downstream, he said, making him unwilling to discard therapies aimed at nitric oxide just yet.

After all, it is possible that the inorganic nitrite could have worked with a longer duration of exposure or perhaps in combination with exercise training, Borlaug said. Oral nitrate is another alternative, as it is converted by bacteria in the mouth to nitrite, that is now being tested in other studies, according to the investigator.

For the INDIE-HFpEF trial, researchers across 20 centers participating in the NHLBI Heart Failure Clinical Research Network randomized 105 participants in their double-blind crossover study. Patients started with 4 weeks on inhaled nitrite or placebo (three times a day) before a switch to 4 weeks on placebo or vice versa.

Heart failure patients were included if they had reduced exercise capacity with New York Heart Association class II-IV symptoms and an ejection fraction of at least 50%. The nitrite-first group had more women and more patients with diabetes.

"That there is an unmet need for a therapy to improve the outcomes of these patients is an understatement," commented James Januzzi, MD, of Massachusetts General Hospital in Boston, at a press conference. "When we say we have few therapies ... we mean we have no therapies to improve outcomes in these patients."

Januzzi said the study was "exceptionally important" while arguing that it doesn't close the door on nitric oxide therapy given its "very strong scientific basis."

"There's still a lot of work to do in this space and the study does point in a direction for us. Someone is going to figure it out sooner or later," he predicted.

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