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Low-Dose Azithromycin May Improve COPD Exacerbation Outcomes

— But larger studies are needed to confirm efficacy, safety

MedpageToday

Treatment with low-dose azithromycin during and after hospitalization for COPD exacerbations was associated with reduced treatment failure, fewer days in the hospital and ICU, and lower mortality in a randomized, multicenter trial from Belgium.

The study examined the impact of giving the macrolide antibiotic during hospitalization for severe acute exacerbation of COPD (AECOPD) and for three months following hospital discharge.

The trial was underpowered to demonstrate statistical significance of time to treatment failure, which was the primary study endpoint, because researchers failed to meet the enrollment goal of 500 patients.

But despite this limitation, findings from the first randomized trial to evaluate macrolide treatment as an acute intervention for patients hospitalized for a severe AECOPD show highly promising results, said principal researcher Win Janssens, MD, PhD of University Hospitals Leuvens in Belgium.

The study, which had 301 participants, appeared in the .

"A positive message of the trial is that our strategy reduced hospital time, days in the ICU, and recurrent exacerbations in the most severe COPD group," Janssens said in a written press statement.

He added that larger, phase 4 studies are needed with hospital readmission as the primary endpoint.

Valerie G. Press, MD, of the University of Chicago, who was not involved with the study, said the strategy of continuing treatment with azithromycin for several months after hospitalization may have been key to reducing recurrent exacerbations.

Press told 鶹ý that azithromycin is commonly used at her hospital in the treatment of acute COPD exacerbations, but only in patients with no contraindications.

"It is important to note that not all patients can safely take macrolides and those identified with contraindications were excluded from the study," she said. "Future work is needed to understand if patients with contraindications to macrolides should be prescribed a different medication."

She agreed that a larger, multi-center study is needed "to fully understand the risks and benefits of this treatment protocol."

"Hospital readmissions are often a proxy for re-exacerbations and could be one primary endpoint to evaluate," she said, adding that overall symptom control, quality of life, and fewer exacerbations would also be critical endpoints to evaluate the efficacy and safety of azithromycin use during and after COPD exacerbations.

Study participants in the azithromycin arm of the study were treated with either 500 mg/day of azithromycin for three days while hospitalized followed by 250 mg of azithromycin twice weekly for three months following discharge in addition to standard care.

Patients with a contraindication to macrolide use were excluded from the study, and the study's primary endpoint -- time to treatment failure -- was defined as a composite of treatment intensification with systemic corticosteroids and/or antibiotics, step-up in hospital care or readmission for respiratory reasons, or patient death.

A total of 147 patients were randomized to the azithromycin arm of the study and 154 patients received standard care with no azithromycin (placebo group).

Among the main findings:

  • The treatment failure rate at three months was 49% in the azithromycin and 60% in the placebo group (HR,0.73; 95% CI 0.53‐1.01, P=0.0526)
  • The treatment intensification rate was 47% in the azithromycin group and 60% in the placebo arm (HR=0.70; 95% CI 0.51-0.97, P=0.0272)
  • Step up hospital care in the azithromycin group was less than half that of the placebo group, 13% versus 28% (HR, 0.43; 95% CI 0.25-0.75, P=0.0024)
  • Mortality rates were 2% in the azithromycin group at three months compared to 4% in the placebo group (HR, 0.62; 95% CI 0.15-2.59, P=0.5057)

The researchers noted that the clinical benefits of treatment with azithromycin appeared to be lost six months after withdrawal.

The researchers wrote that preventing readmissions following an exacerbation "is an international priority aimed at slowing down disease progression and limiting health care costs."

"Apart from the recently published showing a 34% reduction in hospital admissions with ICS, and the REACT trial showing a 24% reduction with phosphodiesterase‐4 inhibitors, no other evidence‐based chronic intervention has demonstrated such a large potential on top of maintenance therapy with long‐acting bronchodilators," they wrote.

Clear convergence of the time‐to‐event curves, six months after withdrawal, "demonstrates that prolonged treatment appears to be needed to sustain its clinical benefits," they added.

"This pleads against our hypothesis that prolonged treatment for three months may sufficiently interrupt the vicious circle of inflammation to alter the phenotype of 'frequent exacerbator.' Cautioned use of intermittent treatment courses of azithromycin is therefore warranted," they concluded.

Disclosures

This research was funded by the Flemish Government Agency for Innovation by Science and Technology.

Lead researcher Kristina Vermeersch reported no industry affiliations. Senior study author Wim Jassens reported receiving research funding and speaker and consultancy fees from Boehringer‐Ingelheim, AstraZeneca, Novartis, Chiesi, and GlaxoSmithKline.

Primary Source

American Journal of Respiratory and Critical Care Medicine

Jassens W, et al "Azithromycin for acute COPD exacerbations requiring hospitalization (BACE): a multicenter randomized, multicenter, placebo controlled trial" AJRCCM 2019.