Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease.

BACKGROUND Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea and a reduction in 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 (PDE4) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. OBJECTIVES To evaluate the efficacy and safety of oral PDE4 inhibitors in the management of stable COPD. SEARCH METHODS We identified randomised controlled trials (RCTs) from the Cochrane Airways Group Specialised Register of trials (date of last search June 2013). We found other trials from web-based clinical trial registers. SELECTION CRITERIA We included RCTs if they compared oral PDE4 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 program (RevMan version 5.2). We reported pooled data as mean differences (MD), standardised mean differences (SMD) or odds ratios (OR). MAIN RESULTS Twenty-nine separate RCTs studying roflumilast (15 trials, 12,654 patients) or cilomilast (14 trials, 6457 patients) met the inclusion criteria, with a duration between six weeks and one year. These included people across international study centres with moderate to very severe COPD (GOLD grades II-IV), with a mean age of 64 years.Treatment with a PDE4 inhibitor was associated with a significant improvement in forced expiratory volume in one second (FEV1) over the trial period compared with placebo (MD 45.60 mL; 95% confidence interval (CI) 39.45 to 51.75, 22 trials with 15,670 participants, moderate quality evidence due to moderate levels of heterogeneity and risk of reporting bias). There were small improvements in quality of life (St George's Respiratory Questionnaire MD -1.04; 95% CI -1.66 to -0.41, 10 trials with 7618 participants, moderate quality evidence due to moderate levels of heterogeneity and risk of reporting bias) and COPD-related symptoms, but no change in exercise tolerance. Treatment with a PDE4 inhibitor was associated with a reduced likelihood of COPD exacerbation (OR 0.77; 95% CI 0.71 to 0.83, high quality evidence). For every 100 people treated with PDE4 inhibitors, six more remained exacerbation-free during the study period compared with placebo (number needed to treat for an additional beneficial effect (NNTB) 20; 95% CI 16 to 27). More participants in the treatment groups experienced non-serious adverse events compared with controls, particularly gastrointestinal symptoms and headache. Roflumilast in particular was associated with weight loss during the trial period and an increase in insomnia and depressive mood symptoms. Participants treated with PDE4 inhibitors were also more likely to withdraw from the trials because of adverse effects; on average 24% in the treatment groups withdrew compared with 19% in the control groups. AUTHORS' CONCLUSIONS In people with COPD, PDE4 inhibitors offered benefit over placebo in improving lung function and reducing the likelihood of exacerbations; however, they had little impact on quality of life or symptoms. Gastrointestinal adverse effects and weight loss were common, and safety data submitted to the US Food and Drug Administration (FDA) have raised concerns over psychiatric adverse events with roflumilast. The optimum place of PDE4 inhibitors in COPD management therefore remains to be defined. Longer-term trials are needed to determine whether or not PDE4 inhibitors modify FEV1 decline, hospitalisation or mortality in COPD.