Azithromycin May Prolong Time to Rehospitalization in COPD

Daniel M. Keller, PhD

June 05, 2013

PHILADELPHIA, Pennsylvania — For patients with chronic obstructive pulmonary disease (COPD), treatment with azithromycin might prolong time to rehospitalization, a new study shows.

"The impact was evident both in time to next all-cause hospitalization and in time to next respiratory hospitalization," said Fernando Martinez, MD, from the University of Michigan at Ann Arbor, "although the impact for respiratory hospitalization was a bit stronger."

Dr. Martinez reported the results here at the American Thoracic Society 2013 International Conference.

In a previous placebo-controlled trial, 1 year of azithromycin therapy reduced exacerbations of COPD (N Engl J Med. 2011;365:689-698). In that trial, there was "a hint" that azithromycin prolonged time to subsequent hospitalization, Dr. Martinez explained. "By hint I mean that for time to exacerbation, the hazard ratio was around 0.7. It was a pretty impressive treatment effect, although there was a small number of events overall."

That trial was not statistically powered to determine the effectiveness of azithromycin in prolonging time to next hospitalization, but it did point to a potential benefit. Previous trials have shown that pharmacotherapy can decrease rates of COPD exacerbations, but have not conclusively shown a decrease in hospitalizations.

Dr. Martinez, who was involved in that trial, and a new team conducted a post hoc analysis of the data.

They randomized stable patients 40 years and older who had an acute exacerbation of COPD in the previous year or who were using supplemental oxygen to receive azithromycin 250 mg once daily or placebo.

The end point of the post hoc analysis was time to rehospitalization during the 1-year study period in patients initially hospitalized for pneumonia, influenza, bronchitis, asthma, or an acute exacerbation of COPD.

Subjects included in the post hoc analysis were about 65 years of age and had a forced expiratory volume in 1 second (FEV1) of about 36% of predicted. About two thirds of the subjects were on oxygen, about 22% were on inhaled corticosteroids and long-acting beta agonists, and more than half were on these drugs plus a long-acting antimuscarinic drug.

Time to a respiratory-related hospitalization was the same for the azithromycin and placebo groups (158 vs 158 days). However, time to initial hospitalization for any cause was longer with azithromycin than with placebo (227 vs 198 days).

Dr. Martinez reported that there was a nonsignificant trend toward prolonged time to subsequent hospitalization for a respiratory problem or for any cause after an initial respiratory-related hospitalization in the azithromycin group.

Table. Risk for Rehospitalization With Azithromycin

Cause of Rehospitalization Hazard Ratio* 95% Confidence Interval P Value
Respiratory-related 0.62 0.38–1.01 .056
Any 0.72 0.47–1.09 .12
*Adjusted for age, sex, smoking status at baseline, and FEV1.


There was no statistically significant difference between the 2 groups in the absolute number of patients who were rehospitalized over the course of the study.

Subjects rehospitalized for a respiratory-related event were similar in the azithromycin (n = 30) and placebo (n = 48) groups in terms of age (64 to 65 years), percent of predicted FEV1 (35% to 36%), sex (58% to 71% men), and inhaled medications.

Dr. Martinez noted that a larger prospective randomized trial is needed to define the absolute number of hospitalization reductions and the number needed to treat if azithromycin has an effect. Because it is a generic drug, any such study would probably need to be sponsored by the National Institutes of Health and would require about 700 hospitalized COPD subjects. Several groups are now proposing such a study.

Dr. Martinez noted that the long-term use of macrolide antibiotics, such as azithromycin, raises safety concerns, including the induction of resistance, the possibility of subtle hearing changes, and a possible impact on cardiovascular events from QTc prolongation.

"This is an approach that is in evolution," he said. "I don't want the message to go out that the datasets that we presented by any means confirm that this approach is validated." Any contemplated chronic use of such antibiotics must fully take into account the inclusion and exclusion criteria of the studies, particularly cardiovascular components, he advised.

The possible beneficial effect of azithromycin began to appear at about 40 to 60 days in this analysis; after that, further rehospitalizations appeared to occur at about the same rate in the 2 groups.

Dr. Martinez proposed that a possible way to minimize adverse effects would be to "target the therapy for a relatively limited period of time after a hospitalization." Three months of therapy would be a good period for a trial, he said.

Antibiotics can play an important role in COPD patients, said David Mannino, MD, from the University of Kentucky in Lexington.

This is becoming the norm in patients with cystic fibrosis. "We borrow some of our best ideas from the worlds of cystic fibrosis and asthma," he told Medscape Medical News. "I can also tell you that, epidemiologically, a severe COPD exacerbation that puts you in the hospital carries a long-term mortality risk that is similar to that of an acute myocardial infarction. For the most part, we've been sort of ignoring this."

According to Dr. Martinez, besides protecting patients from further morbidity, "there is a keen interest right now in addressing the issue of how one can mitigate the risk of a rehospitalization" because Medicare is penalizing institutions if a patient is readmitted within a narrow window of time.

This study was funded by the National Heart, Lung and Blood Institute. Dr. Martinez reports being an advisor to GlaxoSmithKline, Boehringer Ingelheim, Forest Laboratories, and Takeda. Dr. Mannino reports financial relationships with GlaxoSmithKline, Pfizer, Novartis, AstraZeneca, Boehringer Ingelheim, MAP Pharmaceuticals, Dey, and Seprecor.

American Thoracic Society (ATS) 2013 International Conference: Poster J89. Presented May 21, 2013.


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