Roflumilast, an oral selective phosphodiesterase (PDE) 4 inhibitor reduced the rate of moderate or severe exacerbations compared with placebo in patients with chronic obstructive pulmonary di sease (COPD), said Nicola A. Hanania, MD, MS, Director of the Asthma Clinical Research Center, Baylor College of Medicine, Houston, TX.
The effects of roflumilast were more pronounced in patients who had a history of frequent exacerbations and in those with more severe disease, based on a pooled analysis of 2 year-long studies presented at Chest 2010.
“Reduction of the rate of COPD exacerbations may improve overall patient outcomes and result in a reduction of the healthcare burden,” Dr Hanania said.
Because exacerbations are inflammatory events, and PDE 4 may affect multiple inflammatory cells in the lung, a PDE 4 inhibitor could be expected to reduce the number and severity of COPD exacerbations, he said. “Roflumilast targets key proinflammatory mediators underlying the pathogenesis of COPD and associated exacerbations,” Dr Hanania said. Frequent exacerbations (≥2 annually) occur in up to 50% of patients with COPD, depending on their disease severity.
Dr Hanania and colleagues looked at the exacerbation rate and time to exacerbations in 1538 patients with severe COPD and a history of exacerbations who were enrolled in 1 of 2 multicenter, placebo-controlled trials in which they were randomized to roflumilast or placebo for 52 weeks. An exacerbation was defined as new or worsening COPD symptoms that required oral or parenteral glucocorticoids or hospitalization. The results of these trials showed that:
- The rate of moderate or severe exacerbations was reduced by 17% with roflumilast compared with placebo
- The time to a first or second moderate or severe exacerbation was extended in roflumilast recipients by 11% and 21%, respectively
- The rate of moderate or severe exacerbations in the roflumilast groups declined by 18.7% in patients with severe COPD and by 19.7% in those with very severe COPD
- Among patients with 2 or more exacerbations before enrollment in the study, roflumilast reduced the exacerbation rate by 22% compared with placebo, and in those with fewer than 2 exacerbations before study entry, it reduced the exacerbation rate by 16%
- Some 27.7% of placebo patients experienced ≥2 moderate or severe exacerbations during the study compared with 21.4% of the roflumilast groups. The benefit of roflumilast on this end point was observed regardless of disease severity, although the effects were more pronounced in patients with a history of frequent exacerbations and in those with more severe disease.
“Roflumilast has minimal bronchodilatory effects; it’s not a bronchodilator,” Dr Hanania said. “We’re not going to see improvements in FEV1 [forced expiratory volume in 1 second] of 100 mL with roflumilast.” Instead, its benefits can be attributed to its anti-inflammatory activity. As such, he envisions that roflumilast will be used as add-on therapy to long-acting bronchodilators, but it remains to be seen whether it will be used before or after initiation of inhaled corticosteroids as add-on therapy.
Side effects of roflumilast include nausea and other gastrointestinal side effects, as well as weight loss, but none of these have caused withdrawals from clinical studies. The mechanism behind weight loss is still being explored