Chronic obstructive pulmonary disease: An update for the primary physician

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹