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


Large studies have demonstrated that the combination of the short-acting β2-AR agonist albuterol with the short-acting anticholinergic ipratropium is superior to either single agent alone.[109] Some trials have highlighted that the addition of LABAs to ipratropium is more effective than either agent used alone.[110,111] The combination of tiotropium + formoterol has recently been shown to improve FEV1 and FVC more than the ICS/LABA combination salmeterol + fluticasone 500 μg in patients with a baseline FEV1 of 55% predicted.[108] MABA bronchodilators are dimer molecules in which both pharmacologies are present. The LABA/LAMA combination tiotropium + formoterol has also been shown to improve FEV1 AUC, trough FEV1, symptom scores, and rescue medicine use compared with tiotropium alone.[107] Similarly nebulized arformoterol, tiotropium, and the LABA/LAMA arformoterol + tiotropium were compared in a 2-week study. Improvement from baseline of FEV1 AUC, peak FEV1, peak FVC, inspiratory capacity, and dyspnea measured by TDI (transitional dyspnea index) were similar for the two monotherapies. Treatment with the LABA/LAMA combination was associated with a significantly greater improvement in these variables than either the LABA or LAMA monotherapy.[107] The true advantage of this single agent LABA/LAMA is that it may be more readily coupled with ICS in a single inhaler device.[4]

Triple Therapy (ICS/LABA/LAMA)

Emerging evidence from in vitro studies suggests an interaction between corticosteroid and muscarinic receptors that may provide a rationale for use of anticholinergic/corticosteroid combination therapies.[112] This is illustrated by three studies evaluating the benefits of "triple therapy" (tiotropium, salmeterol, and fluticasone) compared with the three component parts[113,114,115] FEV1, inspiratory capacity (IC), and airway conductance were all significantly greater in the triple combination compared with tiotropium monotherapy and SFC (salmeterol fluticasone combination).[114] Perng et al showed that adding tiotropium in patients with severe COPD already treated with a LABA/ICS combination yielded improvements in FVC, FEV1, IC, and SGRQ.[113] The Canadian Respiratory Clinical Research Consortium in collaboration with the Canadian Thoracic Society evaluated tiotropium monotherapy, tiotropium plus salmeterol, and tiotropium plus SFC.[115] There was no significant difference in the proportion of participants suffering an exacerbation (the primary end point in the study) among the three groups. However, tiotropium + SFC improved lung function and disease-specific quality of life and reduced hospitalization for COPD exacerbations and all-cause hospitalizations compared with tiotropium monotherapy. A more recently published retrospective analysis of veterans treated with tiotropium revealed that ICS + LABA + LAMA therapy was associated with a 40% reduction in mortality compared with treatment with ICS + LABA.[116] The clinical effects of such interaction need to be investigated in future clinical trials.


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