Effect of Inorganic Nitrite on Exercise Capacity in HFpEF Patients

Study Questions:

Does inhaled, nebulized inorganic nitrite enhance peak exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF)?


The study was a multicenter, double-blind, placebo-controlled, two-treatment, crossover trial of 105 patients with HFpEF. Inorganic nitrite or placebo was administered via a 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. The primary endpoint was peak oxygen consumption (peak VO2, ml/kg/min). A 6% increase in peak VO2 represents a minimal clinically important difference (0.6 ml/kg/min for a patient with baseline peak VO2 of 10.0 ml/kg/min). Secondary endpoints 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 (E/e′ ratio, estimated pulmonary artery systolic pressure, and left atrial volume index; lower scores indicate better health for all), ventilatory efficiency (VE/VCO2, lower indicating better health), exercise time (higher indicating better health), N-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) levels, other exercise indices, adverse events, and tolerability. Outcomes were assessed after treatment for 4 weeks.


Approximately 93% of the patients (98/105) who were randomized (median age, 68 years; 56% women) completed the trial. The study authors found that during the nitrite phase, there was no significant difference in mean peak VO2 as compared with the placebo phase (13.5 vs. 13.7 ml/kg/min; difference, −0.20; 95% confidence interval [CI], −0.56 to 0.16; p = 0.27). There were no significant between–treatment phase differences in daily activity levels (5,497 vs. 5,503 accelerometry units; difference, −15; 95% CI, −264 to 234; p = 0.91), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (62.6 vs. 61.9; difference, 1.1; 95% CI, −1.4 to 3.5; p = 0.39), functional class (2.5 vs. 2.5; difference, 0.1; 95% CI, −0.1 to 0.2; p = 0.43), echocardiographic E/e′ ratio (16.4 vs. 16.6; difference, 0.1; 95% CI, −1.2 to 1.3; p = 0.93), and pulmonary artery pressure (37.3 vs. 37.4 mm Hg, difference, 0.8; 95% CI, −1.4 to 3.1; p = 0.47), or NT-proBNP (520 vs. 533 pg/ml; difference, 11; 95% CI, −53 to 75; p = 0.74), ventilatory efficiency during exercise testing (VE/VCO2 slope: 32.7 vs. 33.0; difference, −0.5; 95% CI, −1.1 to 0.1; p = 0.11), or exercise time (10.8 vs. 11.0 minutes; difference, −0.2; 95% CI, −0.5 to 0.2; p = 0.30). A total of 95 patients were asked which period they preferred at the final visit: 45% of patients indicated that they felt better during receipt of nitrite, 34% reported feeling better during receipt of placebo, and 21% had no preference. Worsening HF occurred in three participants (2.9%) during the nitrite phase and eight (7.6%) during the placebo phase.


The authors concluded that among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity.


This well designed clinical trial showed that inhaled inorganic nitrite did not improve exercise capacity in a community cohort of HFpEF patients. Many of these patients tend to be sedentary because of significant comorbidities such as obesity and sleep apnea. Whether inorganic nitrite may be effective in a subset of HFpEF patients who are not obese remains to be evaluated before abandoning this promising therapy.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound, Exercise, Sleep Apnea

Keywords: Accelerometry, Atrial Fibrillation, Blood Pressure, Cardiomyopathies, Echocardiography, Exercise, Exercise Test, Heart Failure, Natriuretic Peptide, Brain, Nitrites, Obesity, Oxygen Consumption, Peptide Fragments, Quality of Life, Sleep Apnea Syndromes, Stroke Volume

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