Effect of Inorganic Nitrite vs Placebo on Exercise Capacity among Patients with Heart Failure with Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial

Barry A. Borlaug*, Kevin J. Anstrom, Gregory D. Lewis, Sanjiv J. Shah, James A. Levine, Gabe A. Koepp, Michael M. Givertz, G. Michael Felker, Martin M. Lewinter, Douglas L. Mann, Kenneth B. Margulies, Andrew L. Smith, W. H.Wilson Tang, David J. Whellan, Horng H. Chen, Victor G. Davila-Roman, Steven McNulty, Patrice Desvigne-Nickens, Adrian F. Hernandez, Eugene BraunwaldMargaret M. Redfield

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

187 Scopus citations


Importance: There are few effective treatments for heart failure with preserved ejection fraction (HFpEF). Short-term administration of inorganic nitrite or nitrate preparations has been shown to enhance nitric oxide signaling, which may improve aerobic capacity in HFpEF. Objective: To determine the effect of 4 weeks' administration of inhaled, nebulized inorganic nitrite on exercise capacity in HFpEF. Design, Setting, and Participants: Multicenter, double-blind, placebo-controlled, 2-treatment, crossover trial of 105 patients with HFpEF. Participants were enrolled from July 22, 2016, to September 12, 2017, at 17 US sites, with final date of follow-up of January 2, 2018. Interventions: Inorganic nitrite or placebo administered via micronebulizer device. During each 6-week phase of the crossover study, participants received no study drug for 2 weeks (baseline/washout) followed by study drug (nitrite or placebo) at 46 mg 3 times a day for 1 week followed by 80 mg 3 times a day for 3 weeks. Main Outcomes and Measures: The primary end point was peak oxygen consumption (mL/kg/min). Secondary end points included daily activity levels assessed by accelerometry, health status as assessed by the Kansas City Cardiomyopathy Questionnaire (score range, 0-100, with higher scores reflecting better quality of life), functional class, cardiac filling pressures assessed by echocardiography, N-terminal fragment of the prohormone brain natriuretic peptide levels, other exercise indices, adverse events, and tolerability. Outcomes were assessed after treatment for 4 weeks. Results: Among 105 patients who were randomized (median age, 68 years; 56% women), 98 (93%) completed the trial. During the nitrite phase, there was no significant difference in mean peak oxygen consumption as compared with the placebo phase (13.5 vs 13.7 mL/kg/min; difference, -0.20 [95% CI, -0.56 to 0.16]; P =.27). There were no significant between-treatment phase differences in daily activity levels (5497 vs 5503 accelerometry units; difference, -15 [95% CI, -264 to 234]; P =.91), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (62.6 vs 61.9; difference, 1.1 [95% CI, -1.4 to 3.5]; P =.39), functional class (2.5 vs 2.5; difference, 0.1 [95% CI, -0.1 to 0.2]; P =.43), echocardiographic E/e′ ratio (16.4 vs 16.6; difference, 0.1 [95% CI, -1.2 to 1.3]; P =.93), or N-terminal fragment of the prohormone brain natriuretic peptide levels (520 vs 533 pg/mL; difference, 11 [95% CI, -53 to 75]; P =.74). Worsening heart failure occurred in 3 participants (2.9%) during the nitrite phase and 8 (7.6%) during the placebo phase. Conclusions and Relevance: Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity. Trial Registration: ClinicalTrials.gov Identifier: NCT02742129.

Original languageEnglish (US)
Pages (from-to)1764-1773
Number of pages10
JournalJAMA - Journal of the American Medical Association
Issue number17
StatePublished - Nov 6 2018

ASJC Scopus subject areas

  • General Medicine


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