Treatment failure and hospital readmissions in severe COPD exacerbations treated with azithromycin versus placebo - a post-hoc analysis of the BACE randomized controlled trial

Abstract

Background: In the BACE trial, a 3-month (3 m) intervention with azithromycin, initiated at the onset of an infectious COPD exacerbation requiring hospitalization, decreased the rate of a first treatment failure (TF); the composite of treatment intensification (TI), step-up in hospital care (SH) and mortality.

Objectives: (1) To investigate the intervention's effect on recurrent events, and (2) to identify clinical subgroups most likely to benefit, determined from the incidence rate of TF and hospital readmissions.

Methods: Enrolment criteria included the diagnosis of COPD, a smoking history of ≥10 pack-years and ≥ 1 exacerbation in the previous year. Rate ratio (RR) calculations, subgroup analyses and modelling of continuous variables using splines were based on a Poisson regression model, adjusted for exposure time.

Results: Azithromycin significantly reduced TF by 24% within 3 m (RR = 0.76, 95%CI:0.59;0.97, p = 0.031) through a 50% reduction in SH (RR = 0.50, 95%CI:0.30;0.81, p = 0.006), which comprised of a 53% reduction in hospital readmissions (RR = 0.47, 95%CI:0.27;0.80; p = 0.007). A significant interaction between the intervention, CRP and blood eosinophil count at hospital admission was found, with azithromycin significantly reducing hospital readmissions in patients with high CRP (> 50 mg/L, RR = 0.18, 95%CI:0.05;0.60, p = 0.005), or low blood eosinophil count (<300cells/μL, RR = 0.33, 95%CI:0.17;0.64, p = 0.001). No differences were observed in treatment response by age, FEV1, CRP or blood eosinophil count in continuous analyses.

Conclusions: This post-hoc analysis of the BACE trial shows that azithromycin initiated at the onset of an infectious COPD exacerbation requiring hospitalization reduces the incidence rate of TF within 3 m by preventing hospital readmissions. In patients with high CRP or low blood eosinophil count at admission this treatment effect was more pronounced, suggesting a potential role for these biomarkers in guiding azithromycin therapy.

Trial registration: ClinicalTrials.gov number. NCT02135354 .

Keywords: CRP; Eosinophil count; Macrolide; Readmission; Recurrent event.

Fig. 1

Incidence rate and rate ratio calculations prior to hospital discharge (day X, median: 6 [Q1-Q3 interquartile range: 4–8] days), within 90 and 270 days of a the primary composite endpoint, treatment failure, b its 3 exclusive subcomponents: treatment intensification, step-up in hospital care and mortality, and c step-up in hospital care’s 2 exclusive subcomponents: transfer to the ICU and hospital readmissions. Abbreviations: ICU, intensive care unit. Note: day x, day of discharge, at the investigator’s discretion; day 90, end of intervention; day 270, end of follow-up; *, indicates significant difference

Fig. 2

Incidence rate of treatment failure (panels left) and hospital readmissions (panels right) within 3 month by a CRP, and b blood eosinophil count at day of admission. Abbreviations: CRP, C-reactive protein; TF, treatment failure. Note: Plots are depicted from the 10th to 90th percentile of the respective covariates