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 Braunwald, Margaret M Redfield, National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network, 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 Braunwald, Margaret M Redfield, National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network
Abstract
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.
Conflict of interest statement
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Borlaug has received research support from National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), Savara Therapeutics, Medtronic, Mesoblast, GlaxoSmithKline, and Novartis. Dr Anstrom has received an Heart Failure Network Coordinating Center grant. Dr Lewis has received research support from NIH/NHLBI, Savara, Novartis, the American Heart Association, Abbott, and Ironwood, and has consulted for Cytokinetics, Amgen, Sonivie, Ironwood, and Luitpold. Dr Shah has received research grants from Actelion, AstraZeneca, Corvia, and Novartis, and consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ironwood, Merck, Novartis, Pfizer, Sanofi, and United Therapeutics. Dr Givertz has received grants from the NIH/NHLBI. Dr Felker has received grants from the NIH/NHLBI and Merck; nonfinancial support from Savara Therapeutics; grants and personal fees from Amgen, Cytokinetics, and Roche Diagnostics; and personal fees from Novartis, Bristol-Myers Squibb, Innolife, scPharma, EBR Systems, and V-Wave. Dr Mann has received funding from the NIH and has served as a consultant for Novartis, Bristol-Myers Squibb, and LivaNova. Dr Margulies has received grants from Sanofi-Aventis, GlaxoSmithKline, Biosense Webster, Janssen Pharmaceuticals, and Merck, Sharp, and Dohme, and personal fees from Luitpold Pharmaceuticals and MyoKardia Inc. Dr Tang has received grants from the NIH and personal fees from the Advisory Board Company. Dr Chen has received grants from Scios Inc and is the cofounder and chief marketing officer of Zumbro Discovery. Dr Hernandez has received research grants and/or personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKlein, Janssen, Luitpold, Mast Therapeutics, Merck, the NIH/NHLBI, Novartis, the Patient-Centered Outcomes Research Institute, Portola, and has consulted for Amgen, AstraZeneca, Bayer, Boston Scientific, Merck, Novartis, and Pfizer. For the work under consideration, Dr Braunwald reported research grants to his institution from Duke University for his role as chair of the NHLBI-sponsored Heart Failure Network and study drug supplied by Savara Inc. Outside the submitted work, Dr Braunwald reported grant support to his institution from Daiichi Sankyo, AstraZeneca, GlaxoSmithKline, Merck, Novartis, and Duke University; personal fees from consultancies with Theravance, Cardurion, and MyoKardia; uncompensated consultancies and lectures with Merck and Novartis; uncompensated lectures for The Medicines Company; and personal fees for lectures from Medscape. Dr Redfield has received grants from the NIH and nonfinancial support from Savara Inc. No other disclosures were reported.
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Source: PubMed