Oral PDE4 inhibitors in the management of stable COPD

Almost 1.45 million Australians have some form of chronic obstructive pulmonary disease (COPD). This equates to one in seven Australians over 40 suffering from COPD. Typical symptoms of COPD include shortness of breath, wheezing, chest tightness, chronic cough, unintended weight loss, swelling in ankles, feet and legs. The predominant risk factors for COPD are tobacco smoking and other environmental pollutants.^2,3

Pharmacotherapy is used to treat people with COPD, with effects on symptoms, quality of life, or frequency and severity of exacerbations. The main medications for COPD management include short- and long-acting inhaled beta-2 agonists, anticholinergics, corticosteroids and methylxanthines. Exacerbation of COPD includes sustained increase in symptoms which require additional management.⁴ Common triggers of exacerbations include viral infections, bacterial infections and air pollution. This results in an increased airway inflammation, mucus production and acute deterioration in lung function. Non selective phosphodiesterase inhibitors such as theophylline and methylxanthine are both used for the management of COPD. Novel classes of phosphodiesterase inhibitors including selective Phosphodiesterase inhibitors (PDE4) are potentially useful in the management of COPD. The rationale for their use is that the isoenzyme (PDE4) is responsible for airway inflammation and bronchoconstriction, both of which are pathological features of COPD.^5,6 By inhibiting PDE4, airway narrowing and damage from inflammation are prevented. This summary presents the results of a review addressing the effectiveness of novel PDE4 inhibitors (roflumilast and cilomilast) in the management of COPD. These new products are still not available in Australia. However, they do present new treatment options for COPD exacerbations.

Characteristics of studies

Randomised controlled trials comparing PDE4 inhibitors with placebo were included in the review. Participants were also taking other medications for the management of COPD.

Quality of the research

Studies included in the report had a low or unclear risk of bias. Overall, the quality of the evidence ranged from moderate to high depending on the outcomes reported in the studies. The main sources of bias were selective reporting and incomplete outcome of data.

Results

• The following databases were searched: Cochrane Airways Trials Register, MEDLINE Ovid SP 1946 to date; Embase Ovid SP; PsycINFO Ovid SP; AMED EBSCO (Allied and Complementary Medicine. Hand searches of the proceedings of major respiratory conferences were also undertaken.
• The primary outcome measures included the following: changes in lung function from baseline including forced expiratory volume in one second (FEV1), forced vital capacity (FVC) or peak expiratory flow rate (PEF) and quality of life (e.g. total score on St George’s Respiratory Questionnaire (SGRQ)).
• Secondary outcome measures included: incidence of COPD exacerbations, symptoms (breathlessness on Borg and other scales and Shortness of Breath Questionnaire; composite measures (summary symptom score)), exercise tolerance (six-minute walk test), adverse effects (number of participants experiencing one or more adverse event, e.g. gastrointestinal, central nervous system, (CNS) and cardiovascular adverse events, change in weight, withdrawal rates and serious adverse events and mortality.
• There was a total of 34 randomised controlled trials included in the review – 20 studies examining roflumilast with 17,627 participants and 14 studies examining cilomilast with 6,457 participants. The participants had a mean age of 64 years.
• Treatment with a PDE4 inhibitor resulted in 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. This is based on moderate level of evidence.
• 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 7,645 participants). This was based on a moderate quality of evidence.
• Small improvements in COPD-related symptoms were observed, however, there was no significant change in exercise tolerance.
• Participants taking PDE4 inhibitor had a reduced likelihood of COPD exacerbation (OR 0.78, 95% CI 0.73 to 0.83; 23 trials with 19,948 participants) compared to the control group and this was based on a high-quality evidence).
• 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. 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).

Conclusion

Phosphodiesterase inhibitors are associated with improvement in COPD symptoms and exacerbations. Gastrointestinal adverse events were common in the treatment group. Implications for practice Phosphodiesterase inhibitors are beneficial for the short-term management of COPD as they improve lung function and reduce exacerbations. However, they have not been shown to increase life expectancy. Published studies to date have been of one year or less in duration. Studies with longer duration of follow up are needed to ascertain the long term benefit and safety of this new class of medications.

DR HANAN KHALIL is the Director of the Centre for Chronic Disease Management, a collaborating centre of the Joanna Briggs Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, and a reviewer for the consumer group of the Cochrane Collaboration. She is also Editor in Chief of the International Journal of Evidenced Based HealthCare.

The purpose of this evidence summary is to present the best available evidence regarding the effectiveness and safety of oral Phosphodiesterase 4 (PDE4) inhibitors in the management of stable chronic obstructive pulmonary disease (COPD).

For the full review, please refer to: Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2017, Issue 9. Art. No.: CD002309. DOI: 10.1002/14651858.CD002309. pub5.¹

References

1. Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2017, Issue 9. Art. No.: CD002309. DOI: 10.1002/14651858.CD002309.pub5
2. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet 2007;370: 786–96.
3. White AJ, Gompertz S, Stockley RA. Chronic obstructive pulmonary disease. 6: the aetiology of exacerbations of chronic obstructive pulmonary disease. Thorax 2003;58: 73–80
4. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet 2007;370:786–96.
5. Yan JH, Gu WJ, Pan L. Efficacy and safety of roflumilast in patients with stable chronic obstructive pulmonary disease: a meta-analysis. Pulmonary Pharmacology and Therapeutics 2014;27(1):83–9.
6. Vignola A. PDE4 inhibitors in COPD–a more selective approach to treatment. Respiratory Medicine 2004;98(6):495–503.