Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease

Background: Chronic obstructive pulmonary disease (COPD) affects symptoms, lung function, quality of life and life expectancy. Apart from smoking cessation, there are no other treatments that slow lung function decline. Roflumilast and cilomilast are oral phosphodiesterase 4 (PDE(4)) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD.

Objectives: To evaluate the efficacy and safety of PDE(4) inhibitors in the management of people with stable COPD. Outcomes included lung function, quality of life, symptoms, exacerbations and adverse effects.

Search strategy: We identified randomised controlled trials (RCTs) from the Cochrane Airways Group Specialised Register of trials (date of last search 6 August 2010). We found other trials from web-based clinical trial registers.

Selection criteria: We included RCTs if they compared oral PDE(4) inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy.

Data collection and analysis: One review author extracted data and a second review author checked the data, before entry into The Cochrane Collaboration software programme (RevMan version 5.1). We reported pooled data as mean differences (MD), standardised mean differences (SMD), or odds ratios (OR).

Main results: Twenty-three separate RCTs studying roflumilast (nine trials, 9211 patients) or cilomilast (fourteen trials, 6457 patients) met the inclusion criteria. None of the trials exceeded a year in duration.Treatment with a PDE(4) inhibitor was associated with a significant improvement in FEV(1)over the trial period compared with placebo (MD 45.59 mL; 95% confidence interval (CI) 39.15 to 52.03), regardless of COPD severity or concomitant COPD treatment. There were some small improvements in quality of life (St George's Respiratory Questionnaire MD -1.04; 95% CI -1.66 to -0.41) and COPD-related symptoms, but no change in exercise tolerance. Treatment with a PDE(4) inhibitor was associated with a reduced likelihood of COPD exacerbation (OR 0.78; 95% CI 0.72 to 0.85). More participants in the treatment groups experienced non-serious adverse events compared with controls, particularly gastrointestinal symptoms and headache. Roflumilast was associated with weight loss during the trial period.

Authors' conclusions: In people with COPD, PDE(4) inhibitors offered benefit over placebo in improving lung function and reducing likelihood of exacerbations, however, they had little impact on quality of life or symptoms. Gastrointestinal adverse effects and weight loss were common. The optimum place of PDE(4) inhibitors in COPD management remains to be defined. Longer-term trials are needed to determine whether or not PDE(4) inhibitors modify FEV(1) decline, healthcare utilisation or mortality in COPD.