Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy

Abstract

Rationale: Daily azithromycin decreases acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but long-term side effects are unknown.

Objectives: To identify the types of exacerbations most likely to be reduced and clinical subgroups most likely to benefit from azithromycin, 250 mg daily, added to usual care.

Methods: Enrollment criteria included irreversible airflow limitation and AECOPD requiring corticosteroids, emergency department visit, or hospitalization in the prior year or use of supplemental oxygen. Recurrent events and cumulative incidence analyses compared treatment received for AECOPD by randomization group, stratified by subgroups of interest. Cox proportional hazards models estimated treatment effects in subgroups adjusted for age, sex, smoking status, FEV1% predicted, concomitant COPD medications, and oxygen use.

Measurements and main results: Azithromycin was most effective in reducing AECOPD requiring both antibiotic and steroid treatment (n = 1,113; cumulative incidence analysis, P = 0.0002; recurrent events analysis, P = 0.002). No difference in treatment response by sex (P = 0.75), presence of chronic bronchitis (P = 0.19), concomitant inhaled therapy (P = 0.29), or supplemental oxygen use (P = 0.23) was observed. Older age and milder Global Initiative for Chronic Obstructive Lung Disease stage were associated with better treatment response (P = 0.02 and 0.04, respectively). A significant interaction between treatment and current smoking was seen (P = 0.03) and azithromycin did not reduce exacerbations in current smokers (hazard ratio, 0.99; 95% confidence interval, 0.71-1.38; P = 0.95).

Conclusions: Azithromycin is most effective in preventing AECOPD requiring both antibiotic and steroid treatment. Adjusting for confounders, we saw no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Greater efficacy was seen in older patients and milder Global Initiative for Chronic Obstructive Lung Disease stages. We found little evidence of treatment effect among current smokers. Clinical trial registered with www.clinicaltrials.gov (NCT0011986 and NCT00325897).

Trial registration: ClinicalTrials.gov NCT00325897 NCT00011986 NCT00325897.

Keywords: azithromycin; chronic obstructive pulmonary disease; exacerbation; quality of life.

Figure 1.

Plot demonstrating the differences in cumulative incidence of first exacerbations stratified by randomization group and exacerbation type as classified by treatment with antibiotics only, steroids only, or both. This demonstrates that azithromycin’s effectiveness is most evident in preventing exacerbations requiring antibiotics and steroids. *Comparing cumulative incidence in patients who received antibiotics and steroids for their exacerbation between randomization groups, P = 0.0002. Comparisons by randomization group for other exacerbation types were not statistically significant (steroids only, P = 0.68; antibiotics only, 0.41).

Figure 2.

Hazard ratio (HR) for treatment effect for time to first exacerbation by age (solid line) with 95% point-wise confidence interval (dashed lines) (P = 0.02). Model stratified by clinical center and adjusted for sex, smoking status at baseline, FEV₁% predicted at baseline, concomitant medications for chronic obstructive pulmonary disease, and oxygen use.