Azithromycin for Prevention of COPD Exacerbations

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Clinical Question

In patients with COPD and an increased risk of exacerbation, does prophylactic azithromycin reduce the frequency of exacerbations?

Bottom Line

Prophylactic azithromycin reduced the rate of COPD exacerbations and unscheduled office visits, but was associated with hearing decrements in a minority of participants and significantly increased colonization rates of macrolide-resistant bacteria.

Major Points

During the mid-2000s, several small scale trial suggested that macrolide antibiotics could reduce the frequency of COPD exacerbations, theorized to be due to their anti-inflammatory and antibacterial effects. The COPD Clinical Network designed this trial as a large-scale randomized control trial to test these early findings and demonstrated that azithromycin, when added to usual care, reduced median time to first exacerbation (266 days vs 174 days), frequency of exacerbations per patient year (1.83 vs 1.48), and improved quality of life (36% vs 43%). However, the rate of hearing decriments was higher in the azithromycin arm (25%) than the control arm (20%) and the azithromycin arm has nearly twice the rate of macrolide resistance in patients with nasopharyngeal colonization (81% vs 41%).

Guidelines

GOLD: for patients with GOLD D and exacerbations refractory to LAMA/LABA/iCS therapy, consider prophylactic azithromycin UpToDate: for patients with frequency exacerbations despite optimal medical therapy, consider prophylactic azithromycin

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=1,577
    • Azithromycin (n=1,142, 72%)
    • Control (n=572, 28%)
  • Setting: 17 sites in the United States
  • Enrollment: March 1, 2006 to June 30, 2010
  • Mean follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary outcome: risk of COPD exacerbation

Population

Inclusion Criteria

  • COPD
  • high-risk for exacerbation, as defined by any of the following:
    • on continuous oxygen therapy
    • received systemic steroids within the past year
    • visited emergency room within the past year
    • admitted to hospital within the past year
  • Age 40 or older

Exclusion Criteria

  • Recent COPD exacerbation (<4 weeks)
  • Co-morbid asthma
  • HR > 100bpm
  • QTc >450 ms
  • on QT-prolonging medications (except amiodarone)
  • impaired hearing on audiometry

Baseline Characteristics

Comparisons are experimental group (azithromycin) vs. control group (placebo)

  • Age: 65 +/- 9 experimental vs 66 +/- 8 control
  • Female gender: 41% vs 41%
  • White race/ethnicity: 82% vs 80%
  • GOLD stage:
    • I: 0% vs 1%
    • II: 26% vs 26%
    • III: 40% vs 40%
    • IV: 34% vs 33%
  • COPD regimen:
    • none: 10% vs 8%
    • iCS only: 4% vs 6%
    • LAMA only: 6% vs 8%
    • LABA only: 3% vs 1%
    • iCS + LABA: 19% vs 22%
    • iCS + LAMA: 4% vs 5%
    • LABA + LAMA: 5% vs 4%
    • iCS + LAMA + LABA: 49% vs 46%
  • Smoking, pack years: 58 +/- 32 vs 59 +/- 32
  • Smoking, % current: 21% vs 23%

Interventions

  • At enrollment, participants were 1:1 randomized to either the experimental arm (azithromycin 250mg PO daily) or control arm (placebo pill) for one year.
  • At the time of enrollment, 6 months, and 12 months, participants in each group were given St. George's Respiratory Questionairre (SGRQ) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SH-36) to assess quality of life.
  • At each telephone encounter, clinical visit, or hospitalization for any cause, participants were contacted by study personnel to determine if cause was a COPD exacerbation, defined as "cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids."

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Comparisons are experimental group (azithromycin) vs. control group (placebo)

Primary Outcomes

Time to first COPD exacerbation
266 days vs 174 days (HR 0.74, 95% CI 0.63-0.84, P <0.001)

Secondary Outcomes

Hospitalization for any cause
0.74 vs 0.95 (HR 0.94, 95% CI 0.76-1.15, P = 0.52)
Hospitalization related to COPD
0.34 vs 0.49 (HR 0.82; 95% CI 0.64-1.07; P=0.15)
Emergency department or urgent care visit
0.43 vs 0.48 (HR 0.81; 95% CI 0.63-1.04; P=0.09)
Unscheduled office visit
2.46 vs 2.57 (HR 0.85; 95% CI 0.74-0.98; P=0.02)
Intubations
0.02 vs 0.04 (HR 0.79; 95% CI 0.04-1.75; P=0.56

Subgroup Analysis

Adverse Events

Hearing decriment
25% vs 20% (P=0.04)
Macrolide-resistance of nasopharyngeal colonizations at start of study
52% vs 57% (P=0.64)
Macrolide-resistance of nasopharyngeal colonizations at end of study
81% vs 41% (P<0.001)

Criticisms

While this paper demonstrated the efficacy of azithromycin for reducing the time to first exacerbation of COPD (p <0.001) and unscheduled office visits (p <0.001) - and demonstrated multiple trends towards reduced hospitalization and emergency deartment use - the widespread use of azithromycin has been criticized on several grounds. First, the trial showed significant changes in antimicrobial resistance patterns and the widespread use of macrolide antibiotics for patients with COPD - who number more than 10,000,000 in the United States alone - is concerning. Second, while the primary endpoint, time to first exacerbation of COPD, was both statistically and clinically significant, the reductions in office visits, emergency department use, and hospitalization were quite modest. And finally, azithromycin was associated with a 5% higher rate of hearing decriment than the control arm.

Given the adverse effects of long-term macrolide therapy, society guidelines have been cautious to embrace prophylactic marcolide therapy to prevent exacerbations and hospitalizations for COPD to those with refractory disease and multiple hospitalizations.

Funding

This study was funded by the National Institutes of Health.

Further Reading


https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62410-7/fulltext