Randomization to omega-3 fatty acid supplementation and endothelial function in COPD: The COD-Fish randomized controlled trial

Rationale: Studies suggest a pathogenic role of endothelial dysfunction in chronic obstructive lung disease (COPD). Omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation improves endothelial function in other diseases but has not been examined in COPD. Objective: We hypothesized that n-3 PUFA supplementation would improve systemic endothelial function in COPD. We performed a pilot randomized, placebo-controlled, double-blind, phase II superiority trial (NCT00835289). Methods: Adults with moderate and severe stable COPD (79% with emphysema on CT) were randomized to high-dose fish oil capsules or placebo daily for 6 months. The primary endpoint was percent change in brachial artery flow-mediated dilation (FMD) from baseline to 6 months. Secondary endpoints included peripheral arterial tonometry, endothelial microparticles (EMPs), six-minute walk distance, respiratory symptoms, and pulmonary function. Results: Thirty-three of forty randomized participants completed all measurements. Change in FMD after 6 months did not differ between the fish oil and placebo arms (-1.1%, 95% CI -5.0-2.9, p=0.59). CD31⁺ EMPs increased in the fish oil arm (0.9%, 95% CI 0.1-1.7, p=0.04). More participants in the fish oil arm reported at least a 4-point improvement in the St. George's Respiratory Questionnaire (SGRQ) compared to placebo (8 vs. 1; p=0.01). There were no significant changes in other secondary endpoints. There were four serious adverse events determined to be unrelated to the study (3 in the fish oil arm and 1 in the placebo arm). Conclusion: Randomization to n-3 PUFAs for 6 months did not change systemic endothelial function in COPD. Changes in EMPs and SGRQ suggest n-3 PUFAs might have biologic and clinical effects that warrant further investigation.