Long-term macrolide treatment for the prevention of acute exacerbations in COPD: a systematic review and meta-analysis

Abstract

Background: Acute exacerbation of COPD (AECOPD) is associated with an increased hospitalization and mortality. Azithromycin and erythromycin are the recommended drugs to reduce the risk of exacerbations. However, the most suitable duration of therapy and drug-related adverse events are still a matter of debate. The aim of this meta-analysis was to assess the current evidence regarding the efficacy and safety of long-term macrolide treatment for COPD.

Materials and methods: We comprehensively searched PubMed, Embase, the Cochrane Library, and the Web of Science and performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) and retrospective studies.

Results: Eleven RCTs and one retrospective study including a total of 2,151 cases were carried out. Long-term macrolide treatment significantly reduced the total number of cases with one or more exacerbations (OR=0.40; 95% CI=0.24-0.65; P<0.01) and the rate of exacerbations per patient per year (risk ratio [RR]=0.60; 95% CI=0.45-0.78; P<0.01). Subgroup analyses showed that the minimum duration for drug efficacy for both azithromycin and erythromycin therapy was 6 months. In addition, macrolide therapy could improve the St George Respiratory Questionnaire (SGRQ) total score (P<0.01) but did not achieve the level of clinical significance. The frequency of hospitalizations was not significantly different between the treatment and control groups (P=0.50). Moreover, chronic azithromycin treatment was more likely to increase adverse events (P<0.01).

Conclusion: Prophylactic azithromycin or erythromycin treatment has a significant effect in reducing the frequency of AECOPD in a time-dependent manner. However, long-term macrolide treatment could increase the occurrence of adverse events and macrolide resistance. Future large-scale, well-designed RCTs with extensive follow-up are required to identify patients in whom the benefits outweigh risks.

Keywords: AECOPD; adverse events; azithromycin; macrolide.

Figure 1

Flow diagram of studies identified, included, and excluded.

Figure 2

Graph of the bias risk of the enrolled RCTs. Note: The other bias refers to intention-to-treat analysis. Abbreviation: RCT, randomized controlled trail.

Figure 3

Forest plot and meta-analysis of the total number of patients with one or more exacerbations treated with macrolides compared with the control. Abbreviation: M–H, Mantel–Haenszel method.

Figure 4

Forest plot and subgroup analyses of the total number of patients with one or more exacerbations treated with macrolides compared with the control: (A) different types of macrolides and (B) different durations of treatment. Abbreviation: M–H, Mantel–Haenszel method.

Figure 5

Forest plot and meta-analysis of risk ratios for exacerbations per patient per year treated with macrolides compared with the control.

Figure 6

Forest plot and meta-analysis of the total number of patients requiring hospitalization treated with macrolides compared with the control. Abbreviation: M–H, Mantel–Haenszel method.

Figure 7

Forest plot and meta-analysis of the mean differences in change in total SGRQ score among patients treated with macrolides compared with the control. Abbreviation: SGRQ, St George Respiratory Questionnaire.

Figure 8

Forest plot and meta-analysis of the total number of patients who experienced adverse events during follow-up after treatment with macrolides compared with the control. Abbreviation: M–H, Mantel–Haenszel method.

Figure 9

Forest plot and subgroup analyses of the total number of patients who experienced adverse events during follow-up after treatment with macrolides compared with the control: (A) different types of macrolides and (B) different durations of treatment. Abbreviation: M–H, Mantel–Haenszel method.

Figure 9

Forest plot and subgroup analyses of the total number of patients who experienced adverse events during follow-up after treatment with macrolides compared with the control: (A) different types of macrolides and (B) different durations of treatment. Abbreviation: M–H, Mantel–Haenszel method.

Figure 10

Funnel plots illustrating meta-analysis of the total number of patients with one or more exacerbations after treatment with macrolides compared with the control. Abbreviation: SE, standard error.