Update of PDE4 inhibitors review cautiously supports the GOLD COPD guidelines

Phillippa Poole from the University of Auckland and colleagues from Cochrane Airways editorial team at St George’s University of London have updated the Cochrane Review: Phosphodiesterase-4 inhibitors for Chronic obstructive pulmonary disease (COPD).

The team added a total of five new studies from the search run in March 2020. The studies contributed more information to existing findings but made little impact on outcomes described in earlier versions of this review.

Overall, the review included 43 RCTs involving over 24,500 people living with COPD that compared a PDE4 inhibitor with placebo. The included treatments were roflumilast (28 trials with 18,046 people) or cilomilast (14 trials with 6457 people) or tetomilast (1 trial with 84 people). Trial durations varied between six weeks and one year or longer. These trials included people across international study centres with moderate to very severe COPD, and a mean age of 64 years. The review authors judged risks of selection bias, performance bias, and attrition bias as low overall amongst the 39 published and unpublished trials.

Key findings
  • PDE₄ inhibitors offered a small benefit over placebo in improving lung function though this was clinically insignificant.
  • PDE4 inhibitors reduced the likelihood of exacerbations in people with COPD; 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)
  • PDE4 inhibitors had little impact on quality of life or on symptoms.
  • Gastrointestinal adverse effects, diarrhoea, and weight loss were common, and the likelihood of psychiatric symptoms was higher, with roflumilast 500 µg.
  • 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.
  • Results seen in trials published in journals by pharmaceutical companies show greater benefit of these medicines than those that were unpublished.

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 LABA/ICS combinations). More longer‐term trials are needed to determine whether or not PDE₄ inhibitors modify FEV₁ decline, hospitalisation, or mortality in COPD.

For more information
What are PDE4 inhibitors?

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.

What is COPD?

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).
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.

Review PICO

Participants: Adults (over 18 years of age) with COPD, as defined by the American Thoracic Society, the European Respiratory Society, or GOLD, with airflow obstruction evident by spirometry with post-bronchodilator FEV₁/FVC of 0.7 or less (GOLD 2020).
Interventions: Orally administered PDE₄ inhibitor
Control: Placebo
Outcomes: Primary outcomes: Changes in lung function from baseline including FEV₁, FVC, or PEF; quality of life. Secondary outcomes: incidence of COPD exacerbations; symptoms; exercise tolerance; adverse events; serious adverse events, mortality.