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Review
, 9 (9), CD002309

Phosphodiesterase 4 Inhibitors for Chronic Obstructive Pulmonary Disease

Affiliations
Review

Phosphodiesterase 4 Inhibitors for Chronic Obstructive Pulmonary Disease

Jimmy Chong et al. Cochrane Database Syst Rev.

Abstract

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. This is an update of a Cochrane review first published in 2011 and updated in 2013.

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 Trials Register (date of last search October 2016). We found other trials from web-based clinical trials 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. 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.

Main results: 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(GOLD) grades II-IV), with a mean age of 64 years.We considered that the methodological quality of the 34 published and unpublished trials was acceptable overall.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.

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 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.

Conflict of interest statement

Jimmy Chong: none known Phillippa Poole: none known Bonnie Leung: none known

Figures

Figure 1
Figure 1
In the control group 33 people out of 100 had an exacerbation of COPD over 6‐52 weeks, compared to 28 (95% CI 27 to 29) out of 100 for the active treatment group.
Figure 2
Figure 2
In the control group 4 people out of 100 had diarrhoea over 6‐52 weeks, compared to 11 (95% CI 10 to 12) out of 100 for the active treatment group.
Figure 3
Figure 3
Study flow diagram
Figure 4
Figure 4
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figure 5
Figure 5
Funnel plot of comparison: 1 PDE4 inhibitor versus placebo, outcome: 1.6 FEV1 (published versus unpublished).
Analysis 1.1
Analysis 1.1
Comparison 1 PDE4 inhibitor versus placebo, Outcome 1 FEV1 (by drug).
Analysis 1.2
Analysis 1.2
Comparison 1 PDE4 inhibitor versus placebo, Outcome 2 FEV1 (by mean COPD severity).
Analysis 1.3
Analysis 1.3
Comparison 1 PDE4 inhibitor versus placebo, Outcome 3 FEV1 (Roflumilast 500 μg by mean COPD severity).
Analysis 1.4
Analysis 1.4
Comparison 1 PDE4 inhibitor versus placebo, Outcome 4 FEV1 (by study duration).
Analysis 1.5
Analysis 1.5
Comparison 1 PDE4 inhibitor versus placebo, Outcome 5 FEV1 (additional medication).
Analysis 1.6
Analysis 1.6
Comparison 1 PDE4 inhibitor versus placebo, Outcome 6 FEV1 (published versus unpublished).
Analysis 1.7
Analysis 1.7
Comparison 1 PDE4 inhibitor versus placebo, Outcome 7 FEV1 (random‐effects model).
Analysis 1.8
Analysis 1.8
Comparison 1 PDE4 inhibitor versus placebo, Outcome 8 FEV1 (roflumilast 500 μg versus 250 μg).
Analysis 1.9
Analysis 1.9
Comparison 1 PDE4 inhibitor versus placebo, Outcome 9 FVC.
Analysis 1.10
Analysis 1.10
Comparison 1 PDE4 inhibitor versus placebo, Outcome 10 PEF.
Analysis 1.11
Analysis 1.11
Comparison 1 PDE4 inhibitor versus placebo, Outcome 11 SGRQ total score.
Analysis 1.12
Analysis 1.12
Comparison 1 PDE4 inhibitor versus placebo, Outcome 12 SGRQ total score (by published versus unpublished).
Analysis 1.13
Analysis 1.13
Comparison 1 PDE4 inhibitor versus placebo, Outcome 13 SGRQ total score (by duration).
Analysis 1.14
Analysis 1.14
Comparison 1 PDE4 inhibitor versus placebo, Outcome 14 SGRQ total score (by mean COPD severity).
Analysis 1.15
Analysis 1.15
Comparison 1 PDE4 inhibitor versus placebo, Outcome 15 SGRQ symptom score.
Analysis 1.16
Analysis 1.16
Comparison 1 PDE4 inhibitor versus placebo, Outcome 16 Number of participants with one or more exacerbations (by drug).
Analysis 1.17
Analysis 1.17
Comparison 1 PDE4 inhibitor versus placebo, Outcome 17 Number of participants on roflumilast with one or more exacerbations (additional medication).
Analysis 1.18
Analysis 1.18
Comparison 1 PDE4 inhibitor versus placebo, Outcome 18 Exacerbation rate (inverse variance).
Analysis 1.19
Analysis 1.19
Comparison 1 PDE4 inhibitor versus placebo, Outcome 19 Borg Scale.
Analysis 1.20
Analysis 1.20
Comparison 1 PDE4 inhibitor versus placebo, Outcome 20 Summary symptom score.
Analysis 1.21
Analysis 1.21
Comparison 1 PDE4 inhibitor versus placebo, Outcome 21 Shortness of breath questionnaire.
Analysis 1.22
Analysis 1.22
Comparison 1 PDE4 inhibitor versus placebo, Outcome 22 6‐minute walk test.
Analysis 1.23
Analysis 1.23
Comparison 1 PDE4 inhibitor versus placebo, Outcome 23 Number of participants experiencing an adverse effect.
Analysis 1.24
Analysis 1.24
Comparison 1 PDE4 inhibitor versus placebo, Outcome 24 Number of participants experiencing an adverse event (Roflumilast 500 μg versus 250 μg).
Analysis 1.25
Analysis 1.25
Comparison 1 PDE4 inhibitor versus placebo, Outcome 25 Diarrhoea.
Analysis 1.26
Analysis 1.26
Comparison 1 PDE4 inhibitor versus placebo, Outcome 26 Nausea.
Analysis 1.27
Analysis 1.27
Comparison 1 PDE4 inhibitor versus placebo, Outcome 27 Headache.
Analysis 1.28
Analysis 1.28
Comparison 1 PDE4 inhibitor versus placebo, Outcome 28 Vomiting.
Analysis 1.29
Analysis 1.29
Comparison 1 PDE4 inhibitor versus placebo, Outcome 29 Dyspepsia.
Analysis 1.30
Analysis 1.30
Comparison 1 PDE4 inhibitor versus placebo, Outcome 30 Abdominal pain.
Analysis 1.31
Analysis 1.31
Comparison 1 PDE4 inhibitor versus placebo, Outcome 31 Weight loss.
Analysis 1.32
Analysis 1.32
Comparison 1 PDE4 inhibitor versus placebo, Outcome 32 Influenza‐like symptoms.
Analysis 1.33
Analysis 1.33
Comparison 1 PDE4 inhibitor versus placebo, Outcome 33 Upper respiratory tract infection.
Analysis 1.34
Analysis 1.34
Comparison 1 PDE4 inhibitor versus placebo, Outcome 34 Withdrawals due to adverse events.
Analysis 1.35
Analysis 1.35
Comparison 1 PDE4 inhibitor versus placebo, Outcome 35 Non‐fatal serious adverse events.
Analysis 1.36
Analysis 1.36
Comparison 1 PDE4 inhibitor versus placebo, Outcome 36 Mortality.
Analysis 1.37
Analysis 1.37
Comparison 1 PDE4 inhibitor versus placebo, Outcome 37 All psychiatric disorders (roflumilast).
Analysis 1.38
Analysis 1.38
Comparison 1 PDE4 inhibitor versus placebo, Outcome 38 Insomnia and sleep disorders (roflumilast).
Analysis 1.39
Analysis 1.39
Comparison 1 PDE4 inhibitor versus placebo, Outcome 39 Anxiety or anxiety disorder (roflumilast).
Analysis 1.40
Analysis 1.40
Comparison 1 PDE4 inhibitor versus placebo, Outcome 40 Depression (roflumilast).

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