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Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection FractionThe INDIE-HFpEF Randomized Clinical Trial

Educational Objective
To learn whether inhaled inorganic nitrite improves exercise capacity in patients who have heart failure with preserved ejection fraction.
1 Credit CME
Key Points

Question  Does inhaled inorganic nitrite improve exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF)?

Findings  In this randomized clinical trial that included 105 patients with HFpEF, inhaled inorganic nitrite compared with placebo for 4 weeks resulted in an exercise capacity (measured as peak oxygen consumption) of 13.5 vs 13.7 mL/kg/min, a difference that was not statistically significant.

Meaning  Inhaled inorganic nitrite was not effective in improving exercise capacity in patients with HFpEF.

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

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Article Information

Corresponding Author: Barry A. Borlaug, MD, Mayo Clinic and Foundation, 200 First St SW, Rochester, MN 55905 (borlaug.barry@mayo.edu).

Accepted for Publication: September 26, 2018.

Author Contributions: Dr Borlaug had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Borlaug, Anstrom, Lewis, Shah, Levine, Koepp, Givertz, Felker, LeWinter, Smith, Tang, Chen, Davila-Roman, Desvigne-Nickens, Hernandez, Redfield.

Acquisition, analysis, or interpretation of data: Borlaug, Lewis, Shah, Koepp, Givertz, Felker, Mann, Margulies, Smith, Tang, Whellan, Chen, Davila-Roman, McNulty, Hernandez, Braunwald, Redfield.

Drafting of the manuscript: Borlaug, Levine, LeWinter, Mann, Davila-Roman.

Critical revision of the manuscript for important intellectual content: Borlaug, Anstrom, Lewis, Shah, Levine, Koepp, Givertz, Felker, LeWinter, Margulies, Smith, Tang, Whellan, Chen, Davila-Roman, McNulty, Desvigne-Nickens, Hernandez, Braunwald, Redfield.

Statistical analysis: Borlaug, Anstrom, Koepp, McNulty.

Obtained funding: Lewis, Givertz, Felker, Margulies, Smith, Tang, Whellan, Davila-Roman, Hernandez, Braunwald.

Administrative, technical, or material support: Borlaug, Lewis, Levine, Koepp, Chen, Davila-Roman, Desvigne-Nickens, Hernandez.

Supervision: Borlaug, Levine, Koepp, Givertz, Felker, LeWinter, Margulies, Smith, Davila-Roman, Desvigne-Nickens, Hernandez, Braunwald.

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.

Funding/Support: This work was funded by the Heart Failure Clinical Research Network, which is supported by the NHLBI/NIH (grants U10 HL084904 [awarded to the coordinating center], U10 HL110312, U10 HL110337, U10 HL110342, U10 HL110262, U10 HL110297, U10 HL110302, U10 HL110309, U10 HL110336, and U10 HL110338 [awarded to the regional clinical centers]) and Savara Therapeutics.

Role of the Funder/Sponsor: The NHLBI contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Savara Therapeutics provided study supplies and financial support but was not involved in the design or conduct of the study; collection, management, analysis, and interpretation of data; or preparation, review, or approval of the manuscript. Neither the NHLBI nor Savara Therapeutics were involved in manuscript submission.

NHLBI Heart Failure Clinical Research Network Members: In addition to the byline authors, the following individuals participated in the INDIE-HFpEF Study: HFN Member Clinical Centers: Member Clinical Centers: Brigham and Women’s Hospital: Mary Sheehan, MA; Massachusetts General Hospital: Diane Cocca-Spofford, MHA, and Thomas Cunningham, BS; Boston V.A. Healthcare System: Scott Kinlay, PhD, and Samantha Ly, MA; Cleveland Clinic Foundation: Teresa Fonk, BS; Duke University Medical Center: Michael Murphy, MS; Emory University Hospital: Robert T. Cole, MD, and Gail L. Snell, FNP-BC; Mayo Clinic: Janet Gatzke, BSN; Northwestern Memorial Hospital: Sheano Gold; Washington University School of Medicine: Karen Bult, BSN; V.A. St Louis Medical Center: Ilia Halatchev, MD, and Socorro Marie White, BSN; University of Missouri Health System: Cristina Danila, MD, and Vickie Grieshaber, BSN; Thomas Jefferson University Hospital: Kathleen Fitzgerald, MS; Tufts Medical Center: Gordon Huggins, MD, and Nathan Yuen, BS; University of Pennsylvania Health System: Todd Nicklas, BSN; Johns Hopkins Hospital: Nisha Gilotra, MD, and Anita Bacher, DNP; Stony Brook University Medical Center: Javed Butler, MD, and Indre Caikauskaite, MA; and University of Vermont Medical Center: Peter Van Buren, MD, and Marilynn Roth, RN; HFN Data and Safety Monitoring Board: Douglas E. Vaughan, MD (chair), David DeGrazia, PhD, Kathryn Davis Kennedy, PhD, Maryl R. Johnson, MD, Joseph Parrillo, MD, Marc Penn, MD, and Eric A. Rose, MD. Protocol Review Committee: William Abraham, MD (chair), Jiawen Cai, PhD, Michael R. Zile, MD, and Dalane Kitzman, MD. Biomarker Core Lab: University of Vermont: Russell Tracy, PhD, and Rebekah Boyle, MS. Genetics Core Lab: University of Montreal: Jean-Lucien Rouleau, MD, and Simon de Denus, PhD. CPET Core Lab: Massachusetts General Hospital: Gregory Lewis, MD, Diane Cocca-Spofford, MHA, Luke Wooster, BS, and Cole Bailey, BA. Accelerometry Core Lab: Mayo Clinic: James A. Levine, MD, and Gabriel A. Koepp, MHA. Echo Core Lab: Mayo Clinic: Grace Lin, MD, and Jae K. Oh, MD. Coordinating Center: Duke Clinical Research Institute: Eric J. Velazquez, MD, Adam Devore, MD, Lauren Cooper, MD, Jacob Kelly, MD, Andrew Ambrosy, MD, Marat Fudim, MD, Haider Warraich, MD, Stephen J. Greene, MD, Kishan Parikh, MD, Mary Ann Sellers, MSN, Pamela Monds, AAS, Rachel Olson, MS, Teresa Atwood, CCRA, Nancy Wakeley, BS, and Trevorlyn Haddock, BSN.

Data Sharing Statement: See Supplement 4.

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