Mono- and Combination Therapy of Long-acting Bronchodilators and Inhaled Corticosteroids in Advanced COPD

Jill A. Ohar; James F. Donohue


Semin Respir Crit Care Med. 2010;31(3):321-333. 

In This Article

Combination Therapies

Inhaled Glucocorticoids (ICS)/LABA

Current guidelines highlight the fact that for COPD patients uncontrolled by bronchodilator monotherapy, the use of a combination therapy is recommended. The combination of LABA and ICS is the most common in use for both COPD and asthma. The physiological and clinical benefits of LABAs have been shown to be enhanced when administered in conjunction with ICS,[93] which translates into clinical benefits. ICS and LABA combination products have been shown to improve lung function, symptoms, and health status, and they reduce exacerbations in patients with moderate to severe COPD.[94,95,96,97] Combination of more than one class of bronchodilators such as an inhaled anticholinergic with a β2-AR agonist may be more effective than the use of single agents with respect to improvements in lung function, symptoms, and reducing the risk of adverse events.[98,99,100] However, the results of a recent meta-analysis showed that ICS/LABA did not decrease the number of severe exacerbations, all-cause mortality, respiratory mortality, and cardiovascular mortality compared with LABA monotherapy.[101] This meta-analysis showed that the superior FEV1 achieved with the IC/LABA compared with LABA monotherapy was at the expense of a greater frequency of pneumonia. This is in conflict with an earlier analysis of the same database that found that ICS/LABA combination therapy was superior to LABA monotherapy for exacerbation frequency reduction.[102] The onset of action or formoterol is quicker (in 5 minutes) than tiotropium, but it has comparable bronchodilation over 12 hours.[21] Cazzola and coworkers therefore examined the bronchodilator effect of single doses of formoterol 12 μg and tiotropium 18 μg, and formoterol 12 μg + tiotropium 18 μg given together in stable COPD.[103] Formoterol and tiotropium appeared complementary with regard to lung function indices. Van Noord et al[104] explored these effects elicited by 6 weeks of treatment with tiotropium 18 μg once daily in the morning, formoterol 12 μg twice a day, and tiotropium 18 μg + formoterol 12 μg once daily in the morning in patients suffering from moderate-to-severe COPD. Patients receiving combination treatment had a greater improvement in FEV1 and FVC compared with those receiving the individual agents over 24 hours. Tiotropium was superior to formoterol for FEV1 response over 0 to 12 hours (owing to significant differences from 8 to 12 hours), but the two treatments were not significantly different for FEV1 over 12 to 24 hours or 0 to 24 hours. A similar observation was documented from a recently published 2-week study with tiotropium alone or tiotropium plus formoterol once or twice daily following a 2-week pretreatment period with tiotropium. In this study, the use of an additional evening dose of formoterol had clear added benefit compared with once-a-day formoterol.[105] Nebulized formoterol (20 ug) was combined with tiotropium compared with tiotropium with placebo for 6 weeks.[106] This combination yielded a better FEV1 AUC, mean TDI score, and lower SGRQ symptom score compared with tiotropium plus nebulized placebo. Results were similar in a 12-week study where tiotropium was added to formoterol (12 ug) compared with tiotropium alone.[107] A recent study by Rabe and coworkers highlights the superiority of combining two agents from differing bronchodilator classes to a bronchodilator plus an ICS.[108] Tiotropium plus formoterol was compared with salmeterol/fluticasone combination (SFC). After 6 weeks, the 12-hour FEV1 AUC, FVC AUC, and peak FEV1 and FVC were all significantly greater in the group receiving tiotropium plus formoterol.


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