Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease

Jimmy Chong, Bonnie Leung, Phillippa Poole

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. This is an update of a Cochrane review first published in 2011 and updated in 2013. To evaluate the efficacy and safety of oral PDE4 inhibitors in the management of stable COPD. We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search October 2016). We found other trials from web-based clinical trials registers. We included RCTs if they compared oral PDE4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy. One review author extracted data and a second review author checked the data. We reported pooled data in Review Manager as mean differences (MD), standardised mean differences (SMD) or odds ratios (OR). We converted the odds ratios into absolute treatment effects in a 'Summary of findings' table. Thirty-four separate RCTs studying roflumilast (20 trials with 17,627 participants) or cilomilast (14 trials with 6457 participants) met the inclusion criteria, with a duration of between six weeks and one year. These included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II-IV), with a mean age of 64 years.We considered that the methodological quality of the 34 published and unpublished trials was acceptable overall. 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 51.53 mL, 95% confidence interval (CI) 43.17 to 59.90, 27 trials with 20,585 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 (SGRQ), MD -1.06 units, 95% CI -1.68 to -0.43, 11 trials with 7645 participants, moderate-quality evidence due to moderate levels of heterogeneity and risk of reporting bias) and COPD-related symptoms, but no significant change in exercise tolerance. Treatment with a PDE4 inhibitor was associated with a reduced likelihood of COPD exacerbation (OR 0.78, 95% CI 0.73 to 0.83; 23 trials with 19,948 participants, high-quality evidence). For every 100 people treated with PDE4 inhibitors, five more remained exacerbation-free during the study period compared with placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 26). More participants in the treatment groups experienced non-serious adverse events compared with controls, particularly a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting or dyspepsia. For every 100 people treated with PDE4 inhibitors, seven more suffered from diarrhoea during the study period compared with placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). Roflumilast in particular was associated with weight loss during the trial period and an increase in insomnia and depressive mood symptoms. There was no significant effect of treatment on non-fatal serious adverse events (OR 0.99, 95% CI 0.91 to 1.07) or mortality (OR 0.97, 95% CI 0.76 to 1.23), although mortality was a rare event during the trials. Participants treated with PDE4 inhibitors were more likely to withdraw from the trials because of adverse effects; on average 14% in the treatment groups withdrew compared with 8% in the control groups. 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 findings of this review give cautious support to the use of PDE4 inhibitors in COPD. They may be best used as add-on therapy in a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management. This is in accordance with the GOLD 2017 guidelines. Longer-term trials are needed to determine whether or not PDE4 inhibitors modify FEV1 decline, hospitalisation or mortality in COPD.