Preventing Exacerbations of COPD with Azithromycin

A substantial proportion of the cost of treating patients with chronic obstructive pulmonary disease (COPD) can be attributed to acute exacerbations requiring visits to physicians’ offices and emergency departments as well as days lost from work. In addition, compared with patients who do not have acute exacerbations of COPD, those with acute exacerbations are at increased risk for death, a more rapid decline in lung function, and a reduced quality of life. The frequency of acute exacerbations of COPD has been shown to be reduced with inhaled glucocorticoids, long-acting beta2-agonists, and long-acting muscarinic antagonists; however, patients receiving all 3 of these medications are still at risk for as many as 1.4 acute exacerbations per year. Patients with various inflammatory diseases of the airway have benefited from macrolide antibiotics. There have been mixed results in previous small studies testing whether macrolide antibiotics decrease the frequency of acute exacerbations of COPD. Researchers recently conducted a trial to determine whether azithromycin added to a patient’s usual care reduces the frequency of these events. They reported study results in the New England Journal of Medicine [2011;365(8):689-698]. The study was designed as a prospective, parallel-group, placebo-controlled trial. Of the 1577 patients screened, 1142 met inclusion criteria. Patients were recruited from 17 sites associated with 12 academic health centers in the United States and randomly assigned in a 1:1 ratio to receive either 250 mg of azithromycin in 1 daily dose (n=570) or placebo (n=572) for 1 year in addition to usual care. The primary outcome was the time to the first acute exacerbation of COPD, defined as “a complex of respiratory symptoms (increased or new onset) of >1 of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids.” Secondary outcomes included quality of life, nasopharyngeal colonization with selected respiratory pathogens (Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus species, and Moraxella species), and adherence to taking the study drugs as prescribed. A life-table analysis found that in patients receiving azithromycin, the risk of acute exacerbations of COPD was reduced compared with those in the placebo group (P<.001). In the azithromycin group, the median time to first acute exacerbation of COPD was 266 days (95% confidence interval [CI], 227-313) compared with 174 days (95% CI, 143-215) in the placebo group. The hazard ratio of having an acute exacerbation of COPD per patient-year in the azithromycin group compared with the placebo group was 0.73 (95% CI, 0.63-0.84; P<.001). There were 1641 acute exacerbations of COPD during the study: 741 among the patients in the azithromycin group and 900 among the placebo group. The rates of acute exacerbations of COPD per patient-year were 1.48 and 1.83, respectively (P=.01). In addition, the frequency of acute exacerbations per year was lower in the azithromycin group than in the placebo group regardless of the rate of acute exacerbations per patient-year (P=.008 by both Poisson and negative binomial models). For the secondary outcomes, more participants in the azithromycin group had a decrease of at least 4 points in their St. George’s Respiratory Questionnaire score compared with those in the placebo group. There were no consistent changes in the Medical Outcomes Study 36-Item Short-Form Health Survey. Finally, the mean rate of adherence to the study medication was 67.3% in the azithromycin group and 66.9% in the placebo group (P=.84). In terms of adverse events, hearing decrements were seen more often in the azithromycin group compared with the placebo group (25% vs 20%; P=.04). The researchers concluded that “among subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbation and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known.”