Daily Azithromycin Cut Acute COPD Exacerbations in High-Risk Patients

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.