Inhaled inorganic nitrite did not enhance functional capacity for patients with heart failure with preserved ejection fraction (HFpEF), a randomized controlled trial found.
The nebulized agent didn’t significantly improve exercise capacity compared with placebo after 4 weeks (13.5 versus 13.7 mL/kg/min, P=0.27), reported Barry Borlaug, MD, of Mayo Clinic in Rochester, Minnesota, and colleagues in JAMA.
Nor were there any significant differences in other key outcomes between inhaled inorganic nitrite and placebo, as previously reported at the American College of Cardiology meeting in March:
- Daily activity levels (5,497 versus 5,503 accelerometry units, P=0.91)
- Kansas City cardiomyopathy questionnaire clinical summary score: (62.6 versus 61.9 points, P=0.39)
- Functional class: (2.5 for both on a scale of 1 to 4, P=0.43)
- Echocardiographic E/e′ ratio: (16.4 versus 16.6, P=0.93)
- N-terminal fragment of the prohormone brain natriuretic peptide levels: (520 versus 533 pg/mL, P=0.74)
The study’s findings are “in sharp contrast with the previously reported single-dose effects of sodium nitrite, and may be related to its adverse pharmacokinetic profile with chronic administration,” commented Julio Chirinos, MD, PhD, of University of Pennsylvania Perelman School of Medicine in Philadelphia, who was not involved in the study.
Prior positive studies with inorganic nitrate or nitrite had been acute or short-term administration at single centers, Borlaug and co-authors noted.
And “impaired nitric oxide (NO) signaling underlies this disorder of HFpEF, making it an attractive target of therapy,” noted Erin Michos, MD, MHS, of Johns Hopkins School of Medicine in Baltimore, who was not involved in the study.
Organic nitrate supplements had been found to be poorly tolerated and actually reduced patient’s activity levels, Michos noted. “So this novel inhaled nitrate approach (administered through a nebulizer) is interesting because the drug is converted to NO in the setting of hypoxia and acidosis, thus targeting delivery of NO at a time it is most metabolically needed such as during exercise,” Michos continued.
Now with the negative trial results, “inorganic nitrite should not be pursued as a potential clinically useful agent in HFpEF,” Chirinos said to MedPage Today. “It remains to be seen whether orally administered inorganic nitrate can provide therapeutic benefits with sustained administration.”
Limited exercise capacity was a good target, too, as one of the main complaints of HFpEF patients, Michos added. “We currently do not [have] any effective pharmacologic therapies that have success in reducing morbidity and mortality in HFpEF patients like we do with heart failure with reduced ejection fraction.”
The researchers assessed 105 patients who had a median age of 68 years, and 56% were women. Ninety-three percent of the patients finished the multicenter, double-blind, crossover trial. After a 2-week washout, participants received nitrite or placebo using micronebulizer device at 46 mg three times a day for 1 week followed by 80 mg three times a day for 3 weeks. The researchers assessed outcomes after 4 weeks of treatment.
However, therapies targeted at NO shouldn’t be abandoned, Michos argued. The outcomes of this study might be chalked up to “the wrong dose, or wrong duration of therapy, or that one needs exercise training first before it will work.”
Michos also pointed out that “the short half-life might not be enough to have a sustained effect of their hemodynamic profile, although the researchers did administer it right before the exercise testing.”
“I think the really major issue is that HFpEF is a heterogeneous syndrome – it is not just one entity. It has various underlying etiologies and clinical presentations. Which is why there has not been a ‘one size fits all’ effective treatment strategy yet found,” Michos said.
The researchers acknowledge the limitations of their work. The hypothesis for this paper was based on the idea that improved hemodynamics would result in HFpEF patients becoming more physically active and achieving higher peak exercise capacities, Borlaug and colleagues noted. “However, patients with HFpEF and obesity who are habitually sedentary might not experience the effect of improved hemodynamics on symptoms,” the researchers continued.
Another limitation was the use of accelerometry, which measures volitional activity depending on psychosocial factors and motivation along with limitations linked to cardiac insufficiency, Borlaug and colleagues emphasized. “As such, volume of activity might be less apt to improve with interventions targeted to cardiovascular abnormalities alone, without concomitant behavioral and psychosocial interventions.”
There was no assessment of plasma nitrite levels to relate pharmacokinetics to treatment effects. Blood tests, including cGMP levels, were done before the drug was administered, at which point the plasma nitrite levels were at their trough, the researchers noted.
Going forward, efforts need to be made to figure out how “to target the right therapies to the right patients in a more personalized approach, and to do that we need better phenotyping of these patients,” Michos said.
“We desperately need to make progress in this area as HFpEF continues to evolve to be more global, with greater rates of obesity and comorbidities over time. Therefore, we need to embrace the complexity and there is lots more work to do,” Michos concluded. “Try, try, and try again.”
Michos did not report any disclosures.
Chirinos reported relationships with BMS, Merck, Pfizer, Bayer, OPKO, Microsoft, Fukuda Denshi, Sanifit, Ironwood, Akros, Highpoint, Kaydence Pharma, NIH, ACR, AHA, BMS, Microsoft, Fukuda-Denshi, Atcor, Uscom, Unex, and the University of Pennsylvania.