Phosphodiesterase-4 inhibitors for people with chronic obstructive pulmonary disease (COPD)

Background

COPD is a progressive lung condition caused by damage from harmful chemicals breathed in and is predominantly seen in people who smoke tobacco. These chemicals cause inflammation and lung damage and increase mucus production in the lungs. This leads to periods of breathlessness and coughing called exacerbations (or flare-ups). Exacerbations make it harder for people to do their day-to-day tasks. Exacerbations become more frequent and severe over time. People vary in terms of how they are affected by COPD. This is related in part to the severity of the disease but also to differences in response to medicines, as well as fitness and co-existent conditions. For most people, the only way to prevent further lung damage is to stop smoking.

Medicines prescribed to manage COPD generally aim to improve symptoms, reduce exacerbations, or both. In early stages, taking bronchodilators makes breathing easier by relaxing muscles in the lungs and widening airways, allowing more air to move freely into and out of the lungs.

Some long-acting agents may reduce exacerbations. For example, steroid inhalers reduce inflammation in the lungs and thus modestly reduce the number of exacerbations.

Phosphodiesterase-4 (PDE₄) inhibitors are a relatively new class of medicines marketed to improve COPD. They have both bronchodilator and anti-inflammatory effects. Two currently available medicines - roflumilast and cilomilast - are taken as a tablet. We collated and analysed results of existing trials to define the benefits and risks of PDE₄ inhibitors in COPD.

Key results

Data analysis included 42 studies in 24,587 adults with moderate to very severe disease who discontinued other regular COPD medications. Some trials allowed people to carry on using their usual COPD medicines. Most trials were funded by manufacturers of PDE₄ inhibitors.

PDE₄ inhibitors provided a small benefit in improving lung function measurements (forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), and peak expiratory flow (PEF)). PDE₄ inhibitors also reduced the likelihood of COPD-related exacerbations. We found that 28 out of 100 people taking PDE₄ inhibitors every day for a year would experience at least one exacerbation, which was five fewer than for people who did not receive these medicines.

PDE₄ inhibitors provided a small benefit in reducing breathlessness and improving quality of life. Around 5% to 10% of people who received roflumilast or cilomilast reported side effects such as diarrhoea, nausea, and vomiting. We expected that 11 out of 100 people taking PDE₄ inhibitors every day for 39 weeks would experience an episode of diarrhoea, which was seven more than for those not receiving PDE₄ inhibitors. We found that 7 people out of 100 were likely to experience a psychiatric event with roflumilast 500 µg. A two- to three-fold increase in risk of sleep or mood disturbance was found with roflumilast 500 μg, although overall the total number of reported incidents was low. There was no effect on death rates. Effects were the same regardless of the severity of COPD, or whether other medicines for COPD were being taken.

Quality of the evidence

We were moderately certain about data for lung function and quality of life. We were highly certain of evidence for side effects such as diarrhoea and of data for exacerbations.

Results seen in trials published in journals by pharmaceutical companies show greater benefit of these medicines than those that were unpublished. Psychiatric adverse effects data remain unpublished.

Conclusions

We support the use of PDE₄ inhibitors for COPD, but with caution. PDE₄ inhibitors provided a small benefit in improving lung function and reducing the likelihood of COPD exacerbations, but they had little impact on quality of life and COPD symptoms. Side effects including diarrhoea and weight loss were common.

PDE₄ inhibitors may be best used as add-on therapy for a subgroup of people with persistent symptoms or exacerbations despite otherwise optimal COPD management (e.g. people whose condition was not controlled on fixed-dose long-acting beta₂-agonist (LABA) and inhaled corticosteroid (ICS) combinations). This is in accordance with GOLD 2020 guidelines. Longer-term trials are necessary to get a more accurate estimate of the benefits and safety of these medicines over time, including determining whether they slow COPD disease progression.

Authors' conclusions: 

For this current update, five new studies from the 2020 search contributed to existing findings but made little impact on outcomes described in earlier versions of this review.

PDE₄ inhibitors offered a small benefit over placebo in improving lung function and reducing the likelihood of exacerbations in people with COPD; however, they had little impact on quality of life or on symptoms. Gastrointestinal adverse effects and weight loss were common, and the likelihood of psychiatric symptoms was higher, with roflumilast 500 µg.

The findings of this review provide cautious support for the use of PDE₄ inhibitors in COPD. In accordance with GOLD 2020 guidelines, they may have a place as add-on therapy for a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management (e.g. people whose condition is not controlled by fixed-dose long-acting beta₂-agonist (LABA) and inhaled corticosteroid (ICS) combinations). More longer-term trials are needed to determine whether or not PDE₄ inhibitors modify FEV₁ decline, hospitalisation, or mortality in COPD.

Read the full 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, no other treatments that slow lung function decline are available. Roflumilast and cilomilast are oral phosphodiesterase-4 (PDE₄) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This Cochrane Review was first published in 2011, and was updated in 2017 and 2020.

Objectives: 

To evaluate the efficacy and safety of oral PDE₄ inhibitors for management of stable COPD.

Search strategy: 

We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search 9 March 2020). We found other trials at 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: 

We used standard Cochrane methods. Two independent review authors selected trials for inclusion, extracted data, and assessed risk of bias. We resolved discrepancies by involving a third review author. We assessed our confidence in the evidence by using GRADE recommendations. Primary outcomes were change in lung function (minimally important difference (MID) = 100 mL) and quality of life (scale 0 to 100; higher score indicates more limitations).

Main results: 

We found 42 RCTs that met the inclusion criteria and were included in the analyses for roflumilast (28 trials with 18,046 participants) or cilomilast (14 trials with 6457 participants) or tetomilast (1 trial with 84 participants), with a duration between six weeks and one year or longer. These trials included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II to IV), with mean age of 64 years.

We judged risks of selection bias, performance bias, and attrition bias as low overall amongst the 39 published and unpublished trials.

Lung function

Treatment with a PDE₄ inhibitor was associated with a small, clinically insignificant improvement in forced expiratory volume in one second (FEV₁) over a mean of 40 weeks compared with placebo (mean difference (MD) 49.33 mL, 95% confidence interval (CI) 44.17 to 54.49; participants = 20,815; studies = 29; moderate-certainty evidence). Forced vital capacity (FVC) and peak expiratory flow (PEF) were also improved over 40 weeks (FVC: MD 86.98 mL, 95% CI 74.65 to 99.31; participants = 22,108; studies = 17; high-certainty evidence; PEF: MD 6.54 L/min, 95% CI 3.95 to 9.13; participants = 4245; studies = 6; low-certainty evidence).

Quality of life

Trials reported improvements in quality of life over a mean of 33 weeks (St George's Respiratory Questionnaire (SGRQ) MD -1.06 units, 95% CI -1.68 to -0.43; participants = 7645 ; moderate-certainty evidence).

Incidence of exacerbations

Treatment with a PDE₄ inhibitor was associated with a reduced likelihood of COPD exacerbation over a mean of 40 weeks (odds ratio (OR) 0.78, 95% CI 0.73 to 0.84; participants = 20,382; studies = 27; high-certainty evidence), that is, for every 100 people treated with PDE₄ inhibitors, five more remained exacerbation-free during the study period compared with those given placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 27). No change in COPD-related symptoms nor in exercise tolerance was found.

Adverse events

More participants in the treatment groups experienced an adverse effect compared with control participants over a mean of 39 weeks (OR 1.30, 95% CI 1.22 to 1.38; participants = 21,310; studies = 30; low-certainty evidence). Participants experienced a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting, or dyspepsia. Diarrhoea was more commonly reported with PDE₄ inhibitor treatment (OR 3.20, 95% CI 2.74 to 3.50; participants = 20,623; studies = 29; high-certainty evidence), that is, for every 100 people treated with PDE₄ inhibitors, seven more suffered from diarrhoea during the study period compared with those given placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). The likelihood of psychiatric adverse events was higher with roflumilast 500 µg than with placebo (OR 2.13, 95% CI 1.79 to 2.54; participants = 11,168; studies = 15 (COPD pool data); moderate-certainty evidence). Roflumilast in particular was associated with weight loss during the trial period and with an increase in insomnia and depressive mood symptoms.

Participants treated with PDE₄ inhibitors were more likely to withdraw from trial participation; on average, 14% in the treatment groups withdrew compared with 8% in the control groups.

Mortality

No effect on mortality was found (OR 0.98, 95% CI 0.77 to 1.24; participants = 19,786; studies = 27; moderate-certainty evidence), although mortality was a rare event during these trials.

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