• Pulmonary Clinical Trials
• Chronic Obstructive Pulmonary Disease

One year of treatment with azithromycin significantly educed the rate of acute exacerbations of chronic obstructive pulmonary disease (COPD) and improved quality of life (QoL), according to results of a large randomized clinical trial, presented by Richard K. Albert, MD, Denver Health, University of Colorado, Denver, Colorado, USA.

Both the time to first acute exacerbation and the annualized rate of acute exacerbations were significantly lower in the azithromycin group (p<0.0001 and p=0.004, respectively). Scores on a QoL questionnaire that was specific for pulmonary disease showed significant improvement with azithromycin compared with placebo (p<0.006). The incidence of hearing decrement was increased by about 25% with active therapy versus placebo (p=0.002). The findings might help bring some clarity to the role of macrolide antibiotics in the management of COPD.

Although the trial addressed many of the shortcomings of previous studies [Banerjee D et al. Respir Med 2005; Suzuki T et al. Chest 2001; Seemungal TAR et al. Am J Respir Crit Care Med 2008; Yamaya M et al. J Am Geriatr Soc 2008; He Z et al. Respiration 2010], the impact of azithromycin on macrolide resistance in community bacterial flora remains unknown. Macrolide antibiotics have anti-inflammatory and immunomodulatory effects, in addition to antimicrobial properties. Chronic macrolide use has been shown to reduce the rate of exacerbations of cystic fibrosis and improve the status of patients with other types of airway disease, said Dr. Albert.

To examine the role of macrolides in COPD, investigators designed a randomized, placebo-controlled trial to evaluate azithromycin 250 mg/day, added to patients' existing COPD medications. Treatment and follow-up in the azithromycin and placebo groups continued for 1 year after randomization.

Eligible patients were aged >40 years, had moderate to severe COPD, and at least a 10 pack-year history of smoking. Current smokers were able participate in the study. Investigators randomized 1142 patients, and the final analysis included 1117 patients, 996 of whom completed the study. Patients also had an increased risk for acute exacerbations of COPD, defined by current need for O₂, receipt of systemic steroids, hospitalization, or a COPD-related emergency department visit [Niewoehner et al. Ann Intern Med 2005].

The study's primary endpoint was the time to first acute exacerbation of COPD. An acute exacerbation was defined as an acute increase or new onset of cough, sputum, wheezing, dyspnea, or chest tightness that lasted at least 3 days, requiring systemic steroids and/or antibiotics.

Dr. Albert reported that the median time to a first exacerbation was 266 days in the azithromycin group and 174 days in the placebo group, a difference that translated into a hazard ratio of 0.73 (p<0.0001). The azithromycin group had an acute exacerbation rate of 1.48 per year versus 1.83 for the placebo group (p=0.008).

Azithromycin was associated with a significantly greater decrease in total score on the respiratory questionnaire (−2.8 vs −0.6; p<0.006). Additionally, 42.6% of the azithromycin group had at least a 4-point improvement in the questionnaire, compared with 35.8% of the placebo group (p=0.034).

Adverse events and serious adverse events occurred in a similar proportion of patients in the two groups. Significantly more patients in the azithromycin arm discontinued treatment because of hearing decrements (25% vs 20%; p=0.04).

At enrollment, a similar proportion of patients in the two groups were colonized with selected respiratory pathogens. During the study, 12% of azithromycin patients and 28% of the placebo group who were not colonized with selected respiratory pathogens on enrollment became colonized (p<0.001), but more patients who were treated with azithromycin became colonized with resistant pathogens (81% vs 41%; p<0.0001), but Dr. Albert noted that culture results were available for only 55% to 60% of patients with pathogens.

“The rate of acute exacerbations of COPD was higher in this study than in other recent trials,” said Dr. Albert. “That was by intent, however, as we selected patients who were more likely to have acute exacerbations. Of seven previous studies of macrolides in COPD, two showed no benefit and five showed a decrease in acute exacerbations. All of the studies had design concerns, including retrospective and unblinded designs, no concurrent control groups, and small numbers of patients.”

• © 2011 MD Conference Express