O2.2 Phosphodiesterase type-4 inhibitors

Cilomilast and roflumilast which are not currently available in Australia are inhibitors of phosphodiesterase type-4 (PDE-4).  They act by increasing intracellular concentrations of cyclic adenosine monophosphate and causing a range of anti-inflammatory effects.

Placebo controlled studies of up to six months duration (Rennard 2006, Rabe 2005) have found that PDE-4 inhibitors attenuate decline in lung function and quality of life, and decrease exacerbations when compared to placebo [evidence level II].

PDE-4 inhibitors significantly increase the FEV1, by an order of 40 – 100ml, compared to placebo.  Placebo controlled RCTs have now been extended to 52 weeks (Calverley 2009). They confirm a consistent improvement in pre-bronchodilator FEV1 and a 17% reduction in the annual rate of exacerbations with roflumilast. The effects on lung function, exacerbations and breathlessness are additive to those of long acting bronchodilators such as salmeterol and tiotropium (Fabbri 2009) [evidence level II]. A Cochrane meta-analysis (Chong 2013) concluded that although PDE4 inhibitors improve short term lung function and reduce exacerbations (OR 0.78 95% CI 0.72-0.85), they lead, overall, to marginal improvements in health related quality of life and symptoms.

Drug related adverse effects mainly affect the gastrointestinal system; diarrhoea, abdominal pain, nausea and vomiting and weight loss are approximately twice as common in subjects taking PDE-4 inhibitors as in those taking placebo.

PDE-4 inhibitors are promising candidates for the treatment of chronic obstructive pulmonary disease. Further research is required to determine their long-term impact and role when used with other treatments including corticosteroids.

A one year, multicentre, double-blind, randomised controlled trial of once daily roflumilast 500ug versus placebo in addition to a fixed LABA/ICS combination with or without tiotropium found a modest reduction in rate of moderate to severe exacerbations per patient per year, of marginal statistical significance (Martinez 2015). No change in symptoms or CAT score was noted, but there were small improvements in lung function (treatment difference after 52 weeks =56mls). Side effects –  diarrhoea (10% v 4%), weight loss (9% v 3%) and nausea (6% v 2%) – were more troublesome in the active treatment group compared to the control group. 269 patients stopped treatment in the active group (82 because of adverse effects) compared with 192 in the placebo group (29 because of adverse events). Mortality was not different between the groups (2%). This study suggests there may be a role for roflumilast, in addition to combination therapy in a select group of patients with severe COPD and symptoms of chronic bronchitis who continue to experience moderate exacerbations despite combination therapy.  This benefit needs to be balanced with the side effects on a case by case basis.