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Effect of 1-Year Treatment with Roflumilast in Severe Chronic Obstructive Pulmonary Disease

¹ Division of Infection and Immunity, Department of Medicine, Clinical Sciences, University Hospital Aintree, Liverpool, United Kingdom; ² Hospital Arnau de Vilanova, Valencia, Spain; ³ Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada; ⁴ Altana Pharma AG, The Nycomed Group, Konstanz, Germany; and ⁵ Department of Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy

Correspondence and requests for reprints should be addressed to Peter M.A. Calverley, M.D., Aintree Chest Centre, Fazakerley Hospital, Longmoor Lane, Liverpool L97AL, UK. E-mail: pmacal{at}liverpool.ac.uk

Rationale: The oral phosphodiesterase-4 (PDE4) inhibitor, roflumilast, can improve lung function in moderate chronic obstructive pulmonary disease (COPD). Whether treatment is effective in more severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) over a longer period is unknown.

Objectives: To determine whether roflumilast improves lung function and decreases exacerbation frequency over 1 year in patients with stable COPD.

Methods: We conducted a randomized, placebo-controlled, double-blind, parallel-group trial for 1 year. We recruited 1,513 patients (mean post-bronchodilator FEV₁ 41% predicted), 760 receiving oral 500 µg roflumilast and 753 receiving placebo once daily.

Measurements and Main Results: We recorded post-bronchodilator FEV₁, exacerbation rate, St. George's Respiratory Questionnaire total score at the study end point, and number and type of reported adverse events during treatment. Post-bronchodilator FEV₁ increased by 39 ml with roflumilast compared with placebo by 52 weeks (p = 0.001). The mean exacerbation rate was low and comparable in both treatment groups (0.86 vs. 0.92 exacerbations/patient/yr for roflumilast and placebo, respectively). In a retrospective analysis, the exacerbation rate in patients in GOLD stage IV disease was 36% lower in patients treated with roflumilast than in those treated with placebo (1.01 vs. 1.59 exacerbations/patient/year, respectively; p = 0.024). The St. George's Respiratory Questionnaire total score did not differ between treatments. The commonest adverse events related to roflumilast treatment were diarrhea, nausea, and headache, which usually subsided during continued treatment. However, roflumilast resulted in more withdrawals within the first 3 to 4 weeks of administration.

Conclusions: In severe, stable COPD, PDE4 inhibition with roflumilast produced a modest but significant improvement in lung function without changing the exacerbation rate or health status. However, patients with very severe disease experienced fewer exacerbations with roflumilast.

Key Words: antiinflammatory • chronic obstructive pulmonary disease • exacerbations • lung function • phosphodiesterase-4 inhibitor

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The oral phosphodiesterase-4 (PDE4) inhibitor, roflumilast, can improve lung function in moderate chronic obstructive pulmonary disease (COPD). Whether treatment is effective in more severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) over a longer period is unknown. What This Study Adds to the Field In severe, stable COPD, PDE4 inhibition with roflumilast produced a modest but significant improvement in lung function without changing the exacerbation rate or health status. However, patients with very severe disease experienced fewer exacerbations with roflumilast.

 

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