A Randomized, Placebo-Controlled, Double-Blind, Crossover Trial of Inhaled Nitric Oxide in Patients With Mild-to-Severe COPD.

Abstract

Patients with advanced COPD have pulmonary vascular dysfunction and destruction; thus, it is unclear whether they are responsive to selective pulmonary vasodilators. What is the effect of inhaled nitric oxide (iNO) on exercise capacity in patients without hypoxemia with mild-to-severe COPD without pulmonary hypertension, and are there structural and/or functional predictors of response? Sixty-one patients with mild-to-severe COPD (mean FEV₁, 65% ± 18% predicted) were recruited to this randomized, placebo-controlled, double-blind, crossover trial. Assessments included pulmonary function, echocardiography, and quantitative CT scan. Small vessel volume fraction, defined as the vascular volume of blood vessels with a cross-sectional area < 5 mm² (BV5) divided by total vascular volume (TVV), was used as an index of small vessel perfusion or pulmonary vascular pruning. Participants received iNO or placebo (randomized) during 2 separate incremental exercise tests to determine exercise capacity (peak rate of oxygen consumption [Vo₂peak]). The mean effect of iNO on Vo₂peak was 0.36 mL/kg/min (95% CI, -0.18 to 0.89) in an unadjusted linear mixed effects model. In prespecified analyses, there was evidence of iNO effect modification by BV5/TVV, whereby higher BV5/TVV was associated with greater iNO-induced improvement in Vo₂peak (adjusted mean change, 0.14 mL/kg/min; 95% CI, 0.02-0.26 per 1% increment in BV5/TVV), independent of severity of airflow obstruction, pulmonary diffusing capacity, emphysema, or total lung capacity. iNO-induced increases in Vo₂peak were associated with improved ventilatory efficiency and reduced dyspnea (both P < .05). Our results show that despite a null mean effect of iNO on Vo₂peak in unadjusted analysis, a significant drug-induced improvement in Vo₂peak was observed in patients with higher BV5/TVV. Improvements in Vo₂peak with iNO were associated with improved ventilatory efficiency and reduced dyspnea. Our findings suggest a potential COPD pulmonary vascular endotype responsive to inhaled pulmonary vasodilators, characterized by greater small vessel perfusion or less vascular pruning, that is independent of severity of airflow obstruction, diffusing capacity, emphysema, or lung size. ClinicalTrials.gov; No.: NCT03679312; URL: www. gov.