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

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.

Figures

Figure 1.. Flow of Participants Through the Study of Nitrite Delivery in Heart Failure With Preserved Ejection Fraction

aA total of 12 patients did not reach an adequate peak respiratory exchange ratio (≥1.0) during cardiopulmonary exercise testing. bOf the 8 patients failing the run-in, 2 were for low blood pressure, 2 were for anxiety and hyperventilation, and 4 were other symptomatic intolerances that developed following the run-in dose (abdominal discomfort, dizziness, nausea, cough, and shortness of breath). cIn 3 patients, blood pressure levels were too low to administer the nitrite run-in dose. dThe 8 remaining patients were excluded because 4 could not complete the necessary assessments in the specified time window, 2 withdrew consent, 1 reported after consent that heart failure was not their primary limitation, and 1 was found to have an ejection fraction below 50% after obtaining consent. No imputation for missing data was used because the primary analysis model uses all available data and estimates model parameters using maximum likelihood. eThe study drug was permanently discontinued prior to the primary end-point assessment for 8 patients taking inorganic nitrite (2 unable or unwilling to administer treatment, 1 device malfunction, 1 symptom intolerance [dizziness, nausea, lassitude], 1 discontinued due to dyspepsia, 1 family event, 1 withdrew consent, and 1 death), and 5 taking placebo (2 unable or unwilling to administer treatment, 2 symptom intolerance [tremor and diaphoresis; hypotension], and 1 by investigator decision.

Figure 2.. Peak Oxygen Consumption Following Placebo and Nitrite Treatments

A, Box plot showing peak oxygen consumption (V̇o2) measured following treatment in the placebo phase and nitrite phase, as well as the primary end point of the treatment difference between these phases (P = .27 for comparison of treatment difference after adjusting for treatment sequence, period effect, a random effect for each participant, and baseline peak V̇o2). The horizontal line in the box represents the mean. The edges of the boxes are the 25th and 75th quartile values. If there are no outliers, the ends of the whiskers are minimum and maximum values (left and middle). If there is an outlier (right; open circle), the ends of the whiskers are the highest or lowest values that are not outliers. Outliers are defined as values outside of Q1 − 1.5 × (Q3 − Q1) and Q3 + 1.5 × (Q3 − Q1). B, Each vertical bar represents paired data from an individual patient for peak V̇o2 values during the placebo period on (gray line) with bar extending to values during the nitrite period.

Figure 3.. Treatment Differences in the Primary End Point According to Predefined Subgroups

Error bars indicate 95% confidence intervals. P values for subgroup comparisons correspond to test for interaction. BMI indicates body mass index; BP, blood pressure; GFR, glomerular filtration rate; and NT-proBNP, N-terminal fragment of the prohormone brain natriuretic peptide. aTreatment differences shown are after adjustment for treatment sequence, period effect, and baseline peak oxygen consumption values along with a random effect for each participant.