Effects of Roflumilast on subclinical atherosclerosis in COPD - a randomized controlled trial

Abstract

Background: COPD is associated with an excess atherosclerotic risk. Both, COPD and atherosclerosis are mediated by systemic inflammation. Roflumilast, as an anti-inflammatory drug, revealed potential atheroprotective effects in patients with COPD. Aims: To investigate the effects of Roflumilast on subclinical atherosclerosis (i.e. arterial stiffness, endothelial dysfunction) and a potential association with systemic inflammation in COPD. Methods: 80 COPD patients were randomized to receive Roflumilast or placebo for 24 weeks. Arterial stiffness was measured by pulse wave velocity (PWV) and augmentation index (AIx). Endothelial dysfunction was assessed via reactive hyperemia index (RHI), circulating levels of asymmetric dimethylarginine (ADMA) and matrix metalloproteinase-9 (MMP-9). Systemic inflammation was quantified by C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Results: 67 patients completed the study, 33 of which received Roflumilast and 34 received placebo. The primary endpoint, change from baseline PWV, did not show a significant difference between Roflumilast and placebo (1.07 [95% CI 0.98 – 1.17] vs. 0.99 [95% CI 0.91 – 1.08], p = 0.214). Roflumilast did not improve AIx or markers of endothelial dysfunction (RHI, ADMA, MMP-9) and systemic inflammation (CRP, IL-6, TNF-alpha). We observed a significant improvement of 6-minute walking test with Roflumilast compared to placebo (59.2 [95% CI 18.3 – 100] vs. 0.69 [95% CI -39.7 – 42.1], p = 0.045). Conclusions: Our study does not support an atheroprotective effect of Roflumilast. However, there might be an improvement of exercise capacity with Roflumilast in patients with COPD.