PURPOSE: The oral, selective phosphodiesterase 4 inhibitor roflumilast reduces exacerbation rates and improves lung function in patients with chronic obstructive pulmonary disease (COPD). This analysis investigated the impact of disease severity (defined by GOLD FEV1 stratifications) on the benefit of roflumilast added to salmeterol in COPD patients.
METHODS: Moderate-to-severe COPD patients were recruited to this double-blind, randomized, parallel-group study. After a single-blind, 4-week baseline period with salmeterol, 50μ g BID, plus oral placebo QD, patients continued salmeterol and were randomized to concomitant treatment with roflumilast, 500μ g QD (n=466), or placebo QD (n=467), for 24 weeks. The primary outcome variable was mean change in pre-bronchodilator forced expiratory volume in 1 second (FEV1) from baseline to each post-randomization visit. Other outcomes included post-bronchodilator FEV1, other lung function measurements and the rate of moderate/severe exacerbations. Post-hoc analyses segregating patients by baseline spirometric severity (moderate or severe) were conducted.
RESULTS: At baseline, 627 patients had moderate airflow obstruction (roflumilast+salmeterol n=303, placebo+salmeterol n=324) and 303 exhibited severe airflow obstruction (roflumilast+salmeterol n=162, placebo+salmeterol n=141). For the overall population, when compared to placebo+salmeterol, roflumilast+salmeterol significantly improved pre-bronchodilator (49mL; P< 0.0001) and post-bronchodilator FEV1 (60mL; P< 0.0001). In patients with moderate airflow obstruction, roflumilast+salmeterol significantly improved mean pre-bronchodilator (41mL; 95%CI: 15-67; P=0.0022) and post-bronchodilator FEV1 (49mL; 95%CI: 22-75; P=0.0003) compared to placebo+salmeterol. In subjects with severe airflow obstruction, when compared with placebo+salmeterol, roflumilast+salmeterol significantly improved pre-bronchodilator (75mL; 95%CI: 33-116; P=0.0004) and post-bronchodilator FEV1 (78mL; 95%CI: 35-120; P=0.0004). In the overall population, roflumilast+salmeterol treatment significantly reduced rate of moderate/severe exacerbations (36.8%; P=0.0315) compared to placebo+salmeterol. Roflumilast+salmeterol also numerically decreased moderate/severe exacerbation rates in subjects with moderate (37.1%, rate ratio 95%CI: 0.36-1.10) and severe (33.6%, 0.32-1.38) airflow obstruction compared with placebo+salmeterol, but the individual disease severity populations were too small to reach statistical significance.
CONCLUSION: Roflumilast provides additional clinical benefits to COPD patients with moderate-to-severe airflow obstruction independent of baseline spirometric function.
CLINICAL IMPLICATIONS: In COPD patients already receiving salmeterol, concomitant roflumilast can provide further improvement in pulmonary function and clinical outcomes.
DISCLOSURE: Fernando Martinez, Employee Manja Brose, Thomas Larsson and Udo-Michael Goehring are employees of , Nycomed GmbH.; Consultant fee, speaker bureau, advisory committee, etc. Fernando Martinez has participated in a Speaker’s Bureau on COPD related topics for GSK, BI and in Steering Committees on COPD related topics for Nycomed, GSK, and Advisory Boards for Nycomed/Forest, GSK, Novartis; Andrew McIvor is on the speaker bureau for AstraZeneca, GlaxoSmithKlein, Boehringer Ingelheim, Pfizer, Nycomed, Novartis, and Merck .; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. Roflumilast is approved in the European Union for patients with COPD and is under consideration from the FDA in the US.