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



Parasympathetic activity in the large- and medium-size airways is mediated through the muscarinic receptors (M1 and M3) and results in airway smooth-muscle contraction, mucus secretion, and possibly increased ciliary activity. M2 receptors inhibit acetylcholine release from nerve terminals. Increased cholinergic tone is important in the pathogenesis of COPD, contributing both to increased bronchial smooth muscle tone and to mucus hypersecretion.[49,50] Thus anticholinergics reduce airway tone and improve expiratory flow limitation, hyperinflation, and exercise capacity in patients with COPD.

Two anticholinergic bronchodilators are currently available in the United States for clinical use. These are ipratropium bromide and tiotropium. The short-acting anticholinergic agent, ipratropium bromide, acts on all three muscarinic receptors. Its short duration of action requires dosing every 6 hours, and its delayed onset of action (peak at 45 minutes) precludes its use as rescue therapy. Tiotropium also binds to all three receptor subtypes; however, it dissociates rapidly from M2 receptors. In contrast, its dissociation half-life from M3 receptors is close to 35 hours, which results in a prolonged bronchodilatory effect.[51] Its peak bronchodilatory effect is in 1 to 3 hours and continues for up to 32 hours with a dip between 16 and 24 hours related to circadian change. However, its bronchoprotective effect against a bronchospastic agent continues up to 48 hours.[52]

Clinical Benefits

The short-acting ipratropium has for a long time been used as monotherapy or in combination with albuterol in the maintenance therapy of COPD.[16,53,54] Like ipratropium monotherapy, the fixed combination is available in both metered dose inhaler and nebulizer solution. Unlike ipratropium monotherapy, the fixed combination can be used as rescue therapy because of the rapid onset of action of the albuterol component. Several studies have now shown that the use of long-acting bronchodilators is superior in improving health outcomes. The use of tiotropium in patients with COPD results in improved health status, dyspnea, and exercise capacity, and reduced hyperinflation and COPD exacerbation rate in patients with moderate to severe COPD relative to placebo[55,56,57] and ipratropium.[58,59] Data from large long-term trials showed that trough FEV1 increased by 100 to 150 mL, and the peak FEV1 increased by 150 to 200 mL above trough level after inhalation of 18 μg of tiotropium. No loss of efficacy was seen over the course of 1 year of regular treatment with tiotropium. Furthermore, in a multicenter Veterans Administration trial involving 1829 patients with severe COPD, the addition of tiotropium to other COPD therapies significantly reduced acute COPD exacerbations and reduced COPD hospitalizations when compared with placebo.[60] Data from three more recent studies, specifically designed to explore the potential differences between tiotropium and salmeterol, seem to indicate a greater efficacy of tiotropium.[33,61,62] A meta-analysis that contained these studies and others concluded that tiotropium reduced the odds of a COPD exacerbation and related hospitalizations but not pulmonary or all-cause mortality compared with ipratropium and placebo.[63] It yielded greater increases in FEV1 and forced vital capacity (FVC) than ipratropium, placebo, and LABAs. The effect of tioptropium on odds of a COPD exacerbation and related hospitalizations in this meta-analysis were not different from LABAs.[63] A retrospective analysis of two 1-year placebo-controlled trials showed that the increased frequency of exacerbations in the placebo-treated patients was associated with larger annual decrements in FEV1, transitional dyspnea index, and St. George's Respiratory Questionnaire (SGRQ) scores.[64] In a conflicting analysis, Rodrigo and colleagues concluded that tioptropium did decrease the incidence of severe COPD exacerbations compared with LABAs.[24] A more recent study of subjects 65 years of age and older discharged from the hospital with a diagnosis of COPD revealed that all-cause mortality was 20% lower in the tiotropium-treated group compared with those treated with a LABA.[65] A large clinical trial designed to evaluate the effect of tiotropium on the decline of lung function over a 4-year period (UPLIFT) failed to meet its primary end point; however, this study did show a significant mortality benefit at the end of treatment that was lost at the end of the study.[66,67] Consistent with these findings are the results of the longitudinal, population cohort study in Ontario, Canada. This study showed that patients who received tiotropium were 20% less likely to die than those receiving a LABA.[65] Retrospective analysis of the UPLIFT cohort also revealed that tiotropium reduced exacerbation frequency by 14% compared with controls that included not only placebo treatment but also concurrent medications such as ICS and/or LABAs in 62 to 73% during the course of the study.[68]


Usual effects of anticholinergics are dry mouth, an increased risk of glaucoma, and urinary retention; however, the quaternary nitrogen atom prevents them from being systemically absorbed. Therefore, currently available agents when used in recommended doses are generally safe. These agents should also be used with caution in patients with bladder neck obstruction due to prostatism, and patients with glaucoma. The safety of these agents (both long- and short-acting anticholinergics) was questioned by a recent meta-analysis.[69] This study analyzed 13,645 subjects enrolled into 17 trials and found that inhaled anticholinergics significantly increased the risk of myocardial infarction (MI) (RR 1.52, CI 1.04 to 2.22) and cardiovascular death (RR 1.92, CI 1.23 to 3.0). In direct conflict with the results of this meta-analysis is the UPLIFT study, a 4-year, prospective, head-to-head comparison study of tioptropium and placebo.[66] Mortality at the end of the treatment phase was significantly lower in this study in subjects receiving tiotropium compared with placebo.[67] The mortality benefit was lost at the end of the trial of 30 days after cessation of therapy. More recent analysis of pooled data from several authors showed a reduction of all-cause and cardiovascular death as well as reduced rates of MI and stroke in subjects treated with tiotropium compared with controls.[67,68,69,70,71,72]

Nonbronchodilator Effects of Anticholinergics

Some nonbronchodilator effects for the existing anticholinergics have been reported.[73] Furthermore, results from a recent study performed on sputum cells obtained from COPD patients demonstrate that muscarinic receptors may be involved in airway inflammation in subjects with COPD through acetylcholine-induced ERK1/2-dependent leukotriene B4 release.[74] These results suggest that anticholinergic therapy may contribute to reduced neutrophilic inflammation in COPD; however, these findings need to be further evaluated.

Novel Anticholinergics

Several new long-acting anticholinergic agents are under development, and these include LAS-34273 (aclidinium), LAS-35201, GSK656398, GSK233705, and NVA-237 (glycopyrrolate). Although clinical details are still not available, potential advantages of such agents over tiotropium may include a quicker onset of action and a better safety profile.[4] Aclidinium bromide, however, is a long-acting, muscarinic antagonist in phase III development for the maintenance treatment of moderate to severe COPD. In a study that investigated the efficacy and safety of aclidinium to establish the optimal dose, 464 patients with moderate to severe stable COPD were randomized to double-blind, once-daily treatment with aclidinium (25, 50, 100, 200, or 400 μg), placebo, or open-label tiotropium (18 μg) for 4 weeks. Compared with placebo, aclidinium 200 μg and 400 μg significantly increased trough FEV1 on day 29 versus baseline. There was no loss of efficacy from day 1 to day 29. Time to peak FEV1 was 3 hours for aclidinium 100 to 400 μg. Based on these data, aclidinium 200 μg was selected as the investigational dose for future clinical trials in COPD.[75]


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