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Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial

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Summary

Background

Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care.

Methods

We did a randomised, double-blind, placebo-controlled, single-centre trial in the Netherlands between May 19, 2010, and June 18, 2013. Patients (≥18 years) with a diagnosis of COPD who had received treatment for three or more exacerbations in the previous year were randomly assigned, via a computer-generated randomisation sequence with permuted block sizes of ten, to receive 500 mg azithromycin or placebo three times a week for 12 months. Randomisation was stratified by use of long-term, low-dose prednisolone (≤10 mg daily). Patients and investigators were masked to group allocation. The primary endpoint was rate of exacerbations of COPD in the year of treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00985244.

Findings

We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group. The unadjusted exacerbation rate per patient per year was 1·94 (95% CI 1·50–2·52) for the azithromycin group and 3·22 (2·62–3·97) for the placebo group. After adjustment, azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0·58, 95% CI 0·42–0·79; p=0·001). Three (6%) patients in the azithromycin group reported serious adverse events compared with five (11%) in the placebo group. During follow-up, the most common adverse event was diarrhoea in the azithromycin group (nine [19%] patients vs one [2%] in the placebo group; p=0·015).

Interpretation

Maintenance treatment with azithromycin significantly decreased the exacerbation rate compared with placebo and should therefore be considered for use in patients with COPD who have the frequent exacerbator phenotype and are refractory to standard care.

Funding

SoLong Trust.

Introduction

Acute exacerbations of chronic obstructive pulmonary disease (COPD) have important implications for the natural course of COPD and cause high mortality rates in patients with COPD.1 Patients with three or more exacerbations for which hospital admission is needed have a risk of mortality that is four times higher than those with no exacerbations.2 Prevention of exacerbations is therefore an essential strategy, not only for improvement of mortality rates, but also for improvement of health-related quality of life3 and deceleration of further decline of lung function in patients with COPD.4

Prevention of acute exacerbations of COPD with long-term macrolide treatment is a recent development and the beneficial effect of this treatment has been postulated to result from both an antimicrobial and an immunomodulatory effect.5 The largest study to date of this approach showed that long-term treatment with daily azithromycin significantly decreased the frequency of acute exacerbations of COPD.6 However, this study included patients with at least one exacerbation within the previous year and those who were receiving continuous supplemental oxygen without having had any exacerbation. Implementation of this strategy in clinical practice might result in an excessive use of macrolides in patients with COPD. However, the main risk of the increasing consumption of azithromycin is the induction of macrolide resistance in a large group of patients, with the additional risk of induction of resistance to the general population.7 To benefit maximally from macrolide treatment and to reduce the risk of resistance simultaneously, restrictive use of azithromycin is presently warranted.7 Proposals have been made to reserve long-term macrolide treatment for patients with two or more COPD exacerbations;7, 8 however, this recommendation was not supported by findings from clinical studies.

We did the COpd: infLUence of Macrolides on exacerBation freqUency in patientS (COLUMBUS) trial to investigate whether patients with COPD who had three or more exacerbations in the previous year would have a decreased rate of exacerbation when maintenance macrolide treatment was added to standard care.

Section snippets

Study design and participants

The study protocol has been published elsewhere.9 We undertook this prospective, randomised, double-blind, placebo-controlled, single-centre trial at the Amphia Hospital (Breda, the Netherlands) between May 19, 2010, and June 18, 2013. Eligible patients were 18 years or older, had been diagnosed with COPD according to the guidelines of the Global initiative for chronic Obstructive Lung Disease,10 and had received treatment for three or more exacerbations of COPD in the previous year for which

Results

Figure 1 shows the trial profile. We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. All 92 patients received at least one dose of the assigned treatment (figure 1). In 91 (99%) patients bronchiectasis was excluded by chest CT scan. Table 1 shows baseline characteristics.

We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group (table 2). 13

Discussion

This study is the first to investigate macrolide treatment in patients with frequent exacerbations of COPD. Our findings show that treatment with azithromycin for 12 months decreased the rate of exacerbations and increased time to first exacerbation compared with placebo (panel).

We examined a COPD population who were refractory to usual care. The proportions of patients who received treatment with inhaled corticosteroids (92%), long-acting beta agonists (LABAs) (93%), and long-acting muscarinic

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