Background of the review
Chronic obstructive pulmonary disease (COPD) is a progressive lung condition caused by damage from harmful chemicals that are breathed in and is predominantly seen in people who smoke tobacco. These chemicals set up a cascade of inflammatory reactions, which damage structures in the lung but also increase mucus production in the airways. These processes lead to intermittent symptoms of breathlessness and decreased capacity to perform day-to-day tasks. In addition, people with COPD are at greater risk of developing exacerbations ('flare ups'), which become more frequent and severe over time. People vary in terms of how they are affected by COPD. This is in part related to the severity of the disease but also to differences in response to medicines, an individual's fitness and coexistent conditions. The only way to prevent further lung damage in most people is to stop smoking.
Medicines prescribed to manage COPD generally aim to improve symptoms, reduce exacerbations or both. In the early stages, bronchodilator medicines are helpful because these relax the small muscles in the airway allowing more air to move freely in and out of the lungs. Some long-acting agents may reduce exacerbations. Steroid-containing inhalers may be added specifically to target inflammation in the lungs and thus modestly reduce the number of exacerbations.
Phosphodiesterase 4 (PDE4) inhibitors are a relatively new class of medicines that have been marketed to improve COPD. They have both bronchodilator and anti-inflammatory effects. Moreover, the two currently available medicines, roflumilast and cilomilast, are taken as a tablet. Our review collated and analysed existing trials to define the benefits and risks of PDE4 inhibitors in COPD.
What did we look at?
We found 34 completed trials involving 24,084 adults, with results reported up to October 2016. These consisted mainly of trials in people with moderate to very severe disease who discontinued other regular COPD medications. However, there were seven trials that allowed continuation of usual COPD medicines. The trials ranged from 6 to 52 weeks' duration and the average age of participants was 64 years. The trials were all sponsored by the manufacturers of PDE4 inhibitors.
What did we find out?
Compared with placebo, these medicines provide a small improvement in lung function measurements and reduce the likelihood of an exacerbation of COPD. Based on these results, we would expect that out of 100 people who took PDE4 inhibitors every day for a year, 28 would experience at least one exacerbation which is five fewer than for others who did not receive these medicines.
However, people reported that these medicines only provided a small effect on levels of breathlessness and quality of life. Furthermore, around 5% to 10% of people in trials who received roflumilast or cilomilast reported side effects such as diarrhoea, nausea and vomiting. We would expect that out of 100 people who took PDE4 inhibitors every day for a year, 11 would experience diarrhoea, which is seven more than for others who did not receive these medicines. There was also a two- to three-fold increase in the risk of sleep or mood disturbance for the roflumilast 500 μg dose, although overall the total number of reported incidents was still small. There was no effect on rates of hospitalisation and deaths. The effects were the same regardless of the severity of COPD, or whether other medicines for COPD were being taken.
Quality of the evidence
The studies were generally well designed, as people did not know if they were receiving this new treatment or a placebo medicine. Overall we rated the evidence as being of moderate to high quality.
It is of concern that results seen in trials published in journals by pharmaceutical companies showed a greater benefit of these medicines than those which were unpublished. Therefore, this relies on unpublished trial data being made accessible and up to date. The psychiatric adverse effects data remain unpublished. Longer-term trials are necessary to get a more accurate estimate of the benefits and safety of these medicines over time, including whether they slow COPD disease progression.
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.
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.