LONDON – The benefit of a fixed-dose inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) combination in reducing exacerbations of chronic obstructive pulmonary disease (COPD) far outweighed any risk for pneumonia in a post hoc analysis of the 48-week FORWARD study.
Although there were 13 extra pneumonia events when a fixed-dose combination of beclometasone diproprionate and formoterol fumarate (Foster, Chiesi Farmaceutici SpA) was used as compared to formoterol fumarate alone, there were 123 fewer moderate to severe COPD exacerbations over a 342-day analysis period.
“Analysis of pneumonia and exacerbation cumulative number of events shows that the number of incident pneumonia remains very small relative to that of moderate to severe exacerbations,” Massimo Corradi, MD, of the University of Parma (Italy), reported at the annual congress of the European Respiratory Society.
Dr. Corradi added that the new analysis confirms that the ICS/LABA combination has a “positive risk-benefit balance over LABA monotherapy, supporting [the argument that] the benefits of adding an ICS to a bronchodilator significantly outweigh potential risks.”
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The FORWARD study was a two-arm trial designed to compare the efficacy and safety of fixed-dose treatment with beclometasone diproprionate and formoterol fumarate versus formoterol fumarate alone in 1,199 patients with severe COPD.
For inclusion in the study, patients had to have a post-bronchodilator forced expiratory volume in 1 second below 50% of predicted and a forced vital capacity ratio of less than 0.7. They also had to have a smoking history of 10 pack-years or more, and a history of at least one COPD exacerbation in the previous 12 months that had required treatment or hospitalization (Eur Respir J. 2013;41[1]:12-7).
After a 2-week run-in period, where all patients received a 24-mcg dose of formoterol fumarate, patients were randomized to continue treatment with formoterol fumarate or to receive the fixed-dose combination of beclometasone diproprionate 400 mcg and beclometasone diproprionate 24 mcg for 48 weeks.
A total of 1,186 patients, most of whom were male (69%) with a mean age of 64 years, formed the intention-to-treat population.
Published results (Respir Med. 2014;108[8]:1153-62) showed that the combination of the ICS beclometasone diproprionate and the LABA formoterol fumarate (Chiesi Farmaceutici SpA) was associated with a 28% reduction in the annual rate of moderate to severe exacerbations versus the LABA alone.
The adjusted rate of exacerbations per patient per year was 0.80 in patients treated with the ICS/LABA combination versus 1.12 for those treated with just the LABA, with an adjusted rate ratio of 0.72 (P less than .001).
The published data also showed that pneumonia was reported by 23 patients (3.8%) treated with the ICS/LABA and by 11 (1.8%) treated with the LABA only.
For the new analysis, Dr. Corradi and his coinvestigators looked at the cases of pneumonia and COPD exacerbations in more detail, plotting out the cumulative number of events over time and also characterizing the types of pneumonia in more detail.
All patients had a chest x-ray to confirm the presence of pneumonia, he said, noting that overall there were 35 cases of pneumonia, 24 occurring in patients treated with the fixed-dose beclometasone diproprionate and formoterol fumarate combination and 11 in patients treated only with formoterol fumarate.
Of these cases, 25 required in-hospital treatment – 16 patients in the ICS/LABA arm and 9 in the LABA-only arm. There were three instances of patients acquiring pneumonia in hospital – two in the ICS/LABA and one in the LABA-only arm.
There were also two fatal cases of pneumonia – one in each treatment group. Neither were thought to be related to either of the treatments.
These findings are in line with a recent review of the use of ICS for COPD by the European Medicines Agency (EMA/488280/2016), which noted that “overall the benefits of inhaled corticosteroid medicines in treating COPD continue to outweigh their risks and there should be no change to the way in which these medicines are used.”
The European Medicines Agency advised that patients and clinicians need to “be alert for signs and symptoms of pneumonia, bearing in mind that the clinical features of pneumonia overlap with those of a worsening (exacerbation) of the underlying disease.”
Dr. Corradi has received speaker fees from Chiesi Farmaceutici SpA, which funded the FORWARD study, and his coauthors are employees of the company.