Ted Bosworth

ORLANDO – An atrial fibrillation treatment pathway designed specifically to reduce the proportion of patients with this complaint who are admitted to the hospital from the emergency department was found remarkably effective in a pilot study presented at the annual International AF Symposium.

“In this single-center observational study, a multidisciplinary AF pathway was associated with fivefold reduction in admission rate and 2.5-fold reduction in length of stay for those who were admitted,” reported Jeremy N. Ruskin, MD.

Relative to many other countries, admission rates for AF in the United States are “extremely high,” according to Dr. Ruskin, director of the cardiac arrhythmia service at Massachusetts General Hospital, Boston. Citing 2013 figures from the Nationwide Emergency Department Sample (NEDS) database, rates ranged between 60% and 80% by geographic region with an average of about 66%. In contrast and as an example of lower rates elsewhere, fewer than 40% of AF patients with similar characteristics presenting at emergency departments in Ontario, Can., were admitted. Similarly low admission rates have been reported in Europe.

The AF pathway tested in the study at Mass General was developed through collaboration between electrophysiologists and emergency department physicians. It is suitable for patients presenting with a primary complaint of AF without concomitant diseases, such as sepsis or myocardial infarction. Patients were entered into this study after it was shown that AF was the chief complaint. The first step was to determine whether participants were best suited to a rhythm control or rate control strategy.

“The rhythm control group was anticoagulated and then underwent expedited cardioversion with TEE (transesophageal echocardiogram) if necessary. The rate control group was anticoagulated and then given appropriate pharmacologic therapy,” Dr. Ruskin explained. Once patients were on treatment, an electrophysiologist and an emergency room physician evaluated response. Stable patients were discharged; unstable patients were admitted.

In this nonrandomized observational study conducted over a 1-year period, 94 patients were managed with the AF pathway. Admissions and outcomes in this group were compared with 265 patients who received usual care.

Only 16% of those managed through the AF pathway were admitted versus 80% (P less than .001) in the usual care group. Among those admitted, length of stay was shorter in patients managed along the AF pathway relative to usual care (32 vs. 85 hours; P = .002). Dr. Ruskin also reported that both the cardioversion rate and the proportion of patients discharged on novel oral anticoagulation drugs were higher in the AF pathway group.

The reductions in hospital admissions would be expected to translate into large reductions in costs, particularly as follow-up showed no difference in return visits to the hospital between those entered into the AF pathway relative to those who received routine care, according to Dr. Ruskin. Emphasizing the cost burden of AF admissions, he noted that the estimated charges for the more than 300,000 AF admissions in U.S. hospitals in 2013 exceeded $7 billion.

Currently, there are no guidelines for managing AF in the emergency department, and there is wide variation in practice among centers, according to Dr. Ruskin. He provided data from the NEDS database demonstrating highly significant variations in rates of admission by geographic region (for example, rates were more than 10% higher in the northeast vs. the west) and hospital type (for example, rates were twice as high in metropolitan than nonmetropolitan hospitals).

In the NEDS database, various patient characteristics were associated with increased odds ratios for admission. These included hypertension (OR, 2.3), valvular disease (OR, 3.6), and congestive heart failure (OR, 3.7). However, Dr. Ruskin indicated that patients with these or other characteristics associated with increased likelihood of admission, such as older age, have better outcomes with hospitalization.

The data from this initial observational study were recently published (Am J Cardiol. 2016 Jul 1;118[1]:64-71), and a larger prospective study with this AF pathway is already underway at both Mass General and at Brigham and Women’s Hospital, Boston. If the data confirm that AF admissions can be safely reduced through this pathway, Dr. Ruskin anticipates that implementation will be adopted at other hospitals in the Harvard system.

Dr. Ruskin reported financial relationships with Cardiome, Daiichi Sankyo, Gilead, InCarda Therapeutics, InfoBionic, Laguna Medical, Medtronic, Pfizer, and Portola.

ORLANDO – An atrial fibrillation treatment pathway designed specifically to reduce the proportion of patients with this complaint who are admitted to the hospital from the emergency department was found remarkably effective in a pilot study presented at the annual International AF Symposium.

“In this single-center observational study, a multidisciplinary AF pathway was associated with fivefold reduction in admission rate and 2.5-fold reduction in length of stay for those who were admitted,” reported Jeremy N. Ruskin, MD.

Relative to many other countries, admission rates for AF in the United States are “extremely high,” according to Dr. Ruskin, director of the cardiac arrhythmia service at Massachusetts General Hospital, Boston. Citing 2013 figures from the Nationwide Emergency Department Sample (NEDS) database, rates ranged between 60% and 80% by geographic region with an average of about 66%. In contrast and as an example of lower rates elsewhere, fewer than 40% of AF patients with similar characteristics presenting at emergency departments in Ontario, Can., were admitted. Similarly low admission rates have been reported in Europe.

The AF pathway tested in the study at Mass General was developed through collaboration between electrophysiologists and emergency department physicians. It is suitable for patients presenting with a primary complaint of AF without concomitant diseases, such as sepsis or myocardial infarction. Patients were entered into this study after it was shown that AF was the chief complaint. The first step was to determine whether participants were best suited to a rhythm control or rate control strategy.

“The rhythm control group was anticoagulated and then underwent expedited cardioversion with TEE (transesophageal echocardiogram) if necessary. The rate control group was anticoagulated and then given appropriate pharmacologic therapy,” Dr. Ruskin explained. Once patients were on treatment, an electrophysiologist and an emergency room physician evaluated response. Stable patients were discharged; unstable patients were admitted.

In this nonrandomized observational study conducted over a 1-year period, 94 patients were managed with the AF pathway. Admissions and outcomes in this group were compared with 265 patients who received usual care.

Only 16% of those managed through the AF pathway were admitted versus 80% (P less than .001) in the usual care group. Among those admitted, length of stay was shorter in patients managed along the AF pathway relative to usual care (32 vs. 85 hours; P = .002). Dr. Ruskin also reported that both the cardioversion rate and the proportion of patients discharged on novel oral anticoagulation drugs were higher in the AF pathway group.

The reductions in hospital admissions would be expected to translate into large reductions in costs, particularly as follow-up showed no difference in return visits to the hospital between those entered into the AF pathway relative to those who received routine care, according to Dr. Ruskin. Emphasizing the cost burden of AF admissions, he noted that the estimated charges for the more than 300,000 AF admissions in U.S. hospitals in 2013 exceeded $7 billion.

Currently, there are no guidelines for managing AF in the emergency department, and there is wide variation in practice among centers, according to Dr. Ruskin. He provided data from the NEDS database demonstrating highly significant variations in rates of admission by geographic region (for example, rates were more than 10% higher in the northeast vs. the west) and hospital type (for example, rates were twice as high in metropolitan than nonmetropolitan hospitals).

In the NEDS database, various patient characteristics were associated with increased odds ratios for admission. These included hypertension (OR, 2.3), valvular disease (OR, 3.6), and congestive heart failure (OR, 3.7). However, Dr. Ruskin indicated that patients with these or other characteristics associated with increased likelihood of admission, such as older age, have better outcomes with hospitalization.

The data from this initial observational study were recently published (Am J Cardiol. 2016 Jul 1;118[1]:64-71), and a larger prospective study with this AF pathway is already underway at both Mass General and at Brigham and Women’s Hospital, Boston. If the data confirm that AF admissions can be safely reduced through this pathway, Dr. Ruskin anticipates that implementation will be adopted at other hospitals in the Harvard system.

Dr. Ruskin reported financial relationships with Cardiome, Daiichi Sankyo, Gilead, InCarda Therapeutics, InfoBionic, Laguna Medical, Medtronic, Pfizer, and Portola.

ORLANDO – An atrial fibrillation treatment pathway designed specifically to reduce the proportion of patients with this complaint who are admitted to the hospital from the emergency department was found remarkably effective in a pilot study presented at the annual International AF Symposium.

“In this single-center observational study, a multidisciplinary AF pathway was associated with fivefold reduction in admission rate and 2.5-fold reduction in length of stay for those who were admitted,” reported Jeremy N. Ruskin, MD.

Relative to many other countries, admission rates for AF in the United States are “extremely high,” according to Dr. Ruskin, director of the cardiac arrhythmia service at Massachusetts General Hospital, Boston. Citing 2013 figures from the Nationwide Emergency Department Sample (NEDS) database, rates ranged between 60% and 80% by geographic region with an average of about 66%. In contrast and as an example of lower rates elsewhere, fewer than 40% of AF patients with similar characteristics presenting at emergency departments in Ontario, Can., were admitted. Similarly low admission rates have been reported in Europe.

The AF pathway tested in the study at Mass General was developed through collaboration between electrophysiologists and emergency department physicians. It is suitable for patients presenting with a primary complaint of AF without concomitant diseases, such as sepsis or myocardial infarction. Patients were entered into this study after it was shown that AF was the chief complaint. The first step was to determine whether participants were best suited to a rhythm control or rate control strategy.

“The rhythm control group was anticoagulated and then underwent expedited cardioversion with TEE (transesophageal echocardiogram) if necessary. The rate control group was anticoagulated and then given appropriate pharmacologic therapy,” Dr. Ruskin explained. Once patients were on treatment, an electrophysiologist and an emergency room physician evaluated response. Stable patients were discharged; unstable patients were admitted.

In this nonrandomized observational study conducted over a 1-year period, 94 patients were managed with the AF pathway. Admissions and outcomes in this group were compared with 265 patients who received usual care.

Only 16% of those managed through the AF pathway were admitted versus 80% (P less than .001) in the usual care group. Among those admitted, length of stay was shorter in patients managed along the AF pathway relative to usual care (32 vs. 85 hours; P = .002). Dr. Ruskin also reported that both the cardioversion rate and the proportion of patients discharged on novel oral anticoagulation drugs were higher in the AF pathway group.

The reductions in hospital admissions would be expected to translate into large reductions in costs, particularly as follow-up showed no difference in return visits to the hospital between those entered into the AF pathway relative to those who received routine care, according to Dr. Ruskin. Emphasizing the cost burden of AF admissions, he noted that the estimated charges for the more than 300,000 AF admissions in U.S. hospitals in 2013 exceeded $7 billion.

Currently, there are no guidelines for managing AF in the emergency department, and there is wide variation in practice among centers, according to Dr. Ruskin. He provided data from the NEDS database demonstrating highly significant variations in rates of admission by geographic region (for example, rates were more than 10% higher in the northeast vs. the west) and hospital type (for example, rates were twice as high in metropolitan than nonmetropolitan hospitals).

In the NEDS database, various patient characteristics were associated with increased odds ratios for admission. These included hypertension (OR, 2.3), valvular disease (OR, 3.6), and congestive heart failure (OR, 3.7). However, Dr. Ruskin indicated that patients with these or other characteristics associated with increased likelihood of admission, such as older age, have better outcomes with hospitalization.

The data from this initial observational study were recently published (Am J Cardiol. 2016 Jul 1;118[1]:64-71), and a larger prospective study with this AF pathway is already underway at both Mass General and at Brigham and Women’s Hospital, Boston. If the data confirm that AF admissions can be safely reduced through this pathway, Dr. Ruskin anticipates that implementation will be adopted at other hospitals in the Harvard system.

Dr. Ruskin reported financial relationships with Cardiome, Daiichi Sankyo, Gilead, InCarda Therapeutics, InfoBionic, Laguna Medical, Medtronic, Pfizer, and Portola.

LONDON – Two large phase III trials with lebrikizumab, a monoclonal antibody that blocks the activity of interleukin-13 (IL-13), produced inconsistent evidence of benefit in patients with uncontrolled asthma, according to a presentation of both sets of data at the annual congress of the European Respiratory Society.

The two phase III studies compared lebrikizumab in doses of 37.5 mg and 125 mg to placebo, each administered subcutaneously every 4 weeks. The results were mixed not only for the primary endpoint, which was a reduction in the rate of exacerbations, but also for several secondary outcomes.

Ted Bosworth/Frontline Medical News

LONDON – Two large phase III trials with lebrikizumab, a monoclonal antibody that blocks the activity of interleukin-13 (IL-13), produced inconsistent evidence of benefit in patients with uncontrolled asthma, according to a presentation of both sets of data at the annual congress of the European Respiratory Society.

The two phase III studies compared lebrikizumab in doses of 37.5 mg and 125 mg to placebo, each administered subcutaneously every 4 weeks. The results were mixed not only for the primary endpoint, which was a reduction in the rate of exacerbations, but also for several secondary outcomes.

Ted Bosworth/Frontline Medical News

LONDON – Two large phase III trials with lebrikizumab, a monoclonal antibody that blocks the activity of interleukin-13 (IL-13), produced inconsistent evidence of benefit in patients with uncontrolled asthma, according to a presentation of both sets of data at the annual congress of the European Respiratory Society.

The two phase III studies compared lebrikizumab in doses of 37.5 mg and 125 mg to placebo, each administered subcutaneously every 4 weeks. The results were mixed not only for the primary endpoint, which was a reduction in the rate of exacerbations, but also for several secondary outcomes.

Ted Bosworth/Frontline Medical News

LONDON – Recent evidence of ever smokers having measurable deficits in activity even when lung function is preserved has been further expanded by findings suggesting a different phenotype for patients in this group with radiologic evidence of emphysema, according to data from SPIROMICS (Subpopulations and Intermediate Outcome Measures In COPD Study).

The most recent data were presented at the annual congress of the European Respiratory Society.

Earlier this year, published data drawn from SPIROMICS demonstrated that current and former smokers with preserved lung function (forced expiratory volume in 1 second:forced vital capacity greater than or equal to 0.70) had activity limitations, respiratory symptoms, and exacerbations even though they did not meet the current definition of chronic obstructive pulmonary disease (COPD) (N Engl J Med. 2016;374:1811-21). In the new analysis, further distinctions could be made for patients in this subgroup who also had emphysema on computed tomography (CT).

“Among smokers with preserved lung function, emphysema on CT was associated with reduced activity levels and desaturation on the 6-minute walk test (6MWT),” reported Christian M. Lo Cascio, MD, Columbia University, New York. Compared with smokers with preserved lung function without CT evidence of emphysema, the patients with emphysema on CT did not have more symptoms or exacerbations.

“These and prior findings suggest two distinct but overlapping phenotypes in ever smokers with preserved lung function: an airway disease with respiratory symptoms and frequent exacerbations and emphysema characterized by activity limitation and increased mortality,” said Dr. Lo Cascio.

SPIROMICS, an observational study supported by the National Heart, Lung, and Blood Institute, has enrolled current and former smokers at six centers in the United States to prospectively analyze biomarker, genetic, and clinical data. In the previously published analysis, the focus was on the difference between 849 ever smokers with preserved lung function and 963 patients with mild to moderate COPD. In the data presented by Dr. Lo Cascio, 901 SPIROMICS patients with preserved lung function were analyzed with the focus on the difference between the 66 (7%) who had radiologic evidence of emphysema and the 835 (93%) who had undergone CT indicating that they did not have emphysema.

“Our hypothesis was that the subgroup of patients with emphysema on CT would have lower activity levels, greater desaturation of at least 4% on the 6MWT, more respiratory symptoms, and more exacerbations,” Dr. Lo Cascio reported.

The hypothesis was only half correct. As measured on the activity component of the St. Georges Respiratory Questionnaire, there was about a 10-point (P less than .001) greater reduction in reported activity levels among those with emphysema on CT relative to those without. In addition, the odds ratio (OR) for significant oxygen desaturation, defined as a 4% fall in oxygen saturation of hemoglobin during the 6MWD, was approximately two times greater (P less than .001) for the patients with CT evidence of emphysema.

There were no significant differences between the two groups in walking distance on the 6MWD. Both sets of patients had the same rate of exacerbations and scores on the symptom component of the St. Georges Respiratory Questionnaire, which captures cough, phlegm, wheezing, shortness of breath, and symptom-free days.

Overall, when ever smokers with preserved lung function were subdivided into those with and without CT evidence of emphysema, several similarities were found between the two groups. For those with CT evidence of emphysema and those with no CT evidence of emphysema, mean pack-years of smoking were 43 years and 40 years, respectively, and average body mass indexes were 28.1 and 29.1, respectively. The percentage of patients who had a COPD Assessment Test score of greater than or equal to 10 was 61% among those with CT evidence of emphysema, vs. 50% among those patients without CT evidence of emphysema.

When asked if looking for emphysema on CT in ever smokers with preserved lung function might have clinical utility, Dr. Lo Cascio suggested that it is not yet clear how this information might change management. These data strengthen other evidence from SPIROMICS that ever smokers who do not meet the definition of COPD already have a significant disease burden, he said.

Dr. Lo Cascio reports no relevant financial relationships.

LONDON – Recent evidence of ever smokers having measurable deficits in activity even when lung function is preserved has been further expanded by findings suggesting a different phenotype for patients in this group with radiologic evidence of emphysema, according to data from SPIROMICS (Subpopulations and Intermediate Outcome Measures In COPD Study).

The most recent data were presented at the annual congress of the European Respiratory Society.

Earlier this year, published data drawn from SPIROMICS demonstrated that current and former smokers with preserved lung function (forced expiratory volume in 1 second:forced vital capacity greater than or equal to 0.70) had activity limitations, respiratory symptoms, and exacerbations even though they did not meet the current definition of chronic obstructive pulmonary disease (COPD) (N Engl J Med. 2016;374:1811-21). In the new analysis, further distinctions could be made for patients in this subgroup who also had emphysema on computed tomography (CT).

“Among smokers with preserved lung function, emphysema on CT was associated with reduced activity levels and desaturation on the 6-minute walk test (6MWT),” reported Christian M. Lo Cascio, MD, Columbia University, New York. Compared with smokers with preserved lung function without CT evidence of emphysema, the patients with emphysema on CT did not have more symptoms or exacerbations.

“These and prior findings suggest two distinct but overlapping phenotypes in ever smokers with preserved lung function: an airway disease with respiratory symptoms and frequent exacerbations and emphysema characterized by activity limitation and increased mortality,” said Dr. Lo Cascio.

SPIROMICS, an observational study supported by the National Heart, Lung, and Blood Institute, has enrolled current and former smokers at six centers in the United States to prospectively analyze biomarker, genetic, and clinical data. In the previously published analysis, the focus was on the difference between 849 ever smokers with preserved lung function and 963 patients with mild to moderate COPD. In the data presented by Dr. Lo Cascio, 901 SPIROMICS patients with preserved lung function were analyzed with the focus on the difference between the 66 (7%) who had radiologic evidence of emphysema and the 835 (93%) who had undergone CT indicating that they did not have emphysema.

“Our hypothesis was that the subgroup of patients with emphysema on CT would have lower activity levels, greater desaturation of at least 4% on the 6MWT, more respiratory symptoms, and more exacerbations,” Dr. Lo Cascio reported.

The hypothesis was only half correct. As measured on the activity component of the St. Georges Respiratory Questionnaire, there was about a 10-point (P less than .001) greater reduction in reported activity levels among those with emphysema on CT relative to those without. In addition, the odds ratio (OR) for significant oxygen desaturation, defined as a 4% fall in oxygen saturation of hemoglobin during the 6MWD, was approximately two times greater (P less than .001) for the patients with CT evidence of emphysema.

There were no significant differences between the two groups in walking distance on the 6MWD. Both sets of patients had the same rate of exacerbations and scores on the symptom component of the St. Georges Respiratory Questionnaire, which captures cough, phlegm, wheezing, shortness of breath, and symptom-free days.

Overall, when ever smokers with preserved lung function were subdivided into those with and without CT evidence of emphysema, several similarities were found between the two groups. For those with CT evidence of emphysema and those with no CT evidence of emphysema, mean pack-years of smoking were 43 years and 40 years, respectively, and average body mass indexes were 28.1 and 29.1, respectively. The percentage of patients who had a COPD Assessment Test score of greater than or equal to 10 was 61% among those with CT evidence of emphysema, vs. 50% among those patients without CT evidence of emphysema.

When asked if looking for emphysema on CT in ever smokers with preserved lung function might have clinical utility, Dr. Lo Cascio suggested that it is not yet clear how this information might change management. These data strengthen other evidence from SPIROMICS that ever smokers who do not meet the definition of COPD already have a significant disease burden, he said.

Dr. Lo Cascio reports no relevant financial relationships.

LONDON – Recent evidence of ever smokers having measurable deficits in activity even when lung function is preserved has been further expanded by findings suggesting a different phenotype for patients in this group with radiologic evidence of emphysema, according to data from SPIROMICS (Subpopulations and Intermediate Outcome Measures In COPD Study).

The most recent data were presented at the annual congress of the European Respiratory Society.

Earlier this year, published data drawn from SPIROMICS demonstrated that current and former smokers with preserved lung function (forced expiratory volume in 1 second:forced vital capacity greater than or equal to 0.70) had activity limitations, respiratory symptoms, and exacerbations even though they did not meet the current definition of chronic obstructive pulmonary disease (COPD) (N Engl J Med. 2016;374:1811-21). In the new analysis, further distinctions could be made for patients in this subgroup who also had emphysema on computed tomography (CT).

“Among smokers with preserved lung function, emphysema on CT was associated with reduced activity levels and desaturation on the 6-minute walk test (6MWT),” reported Christian M. Lo Cascio, MD, Columbia University, New York. Compared with smokers with preserved lung function without CT evidence of emphysema, the patients with emphysema on CT did not have more symptoms or exacerbations.

“These and prior findings suggest two distinct but overlapping phenotypes in ever smokers with preserved lung function: an airway disease with respiratory symptoms and frequent exacerbations and emphysema characterized by activity limitation and increased mortality,” said Dr. Lo Cascio.

SPIROMICS, an observational study supported by the National Heart, Lung, and Blood Institute, has enrolled current and former smokers at six centers in the United States to prospectively analyze biomarker, genetic, and clinical data. In the previously published analysis, the focus was on the difference between 849 ever smokers with preserved lung function and 963 patients with mild to moderate COPD. In the data presented by Dr. Lo Cascio, 901 SPIROMICS patients with preserved lung function were analyzed with the focus on the difference between the 66 (7%) who had radiologic evidence of emphysema and the 835 (93%) who had undergone CT indicating that they did not have emphysema.

“Our hypothesis was that the subgroup of patients with emphysema on CT would have lower activity levels, greater desaturation of at least 4% on the 6MWT, more respiratory symptoms, and more exacerbations,” Dr. Lo Cascio reported.

The hypothesis was only half correct. As measured on the activity component of the St. Georges Respiratory Questionnaire, there was about a 10-point (P less than .001) greater reduction in reported activity levels among those with emphysema on CT relative to those without. In addition, the odds ratio (OR) for significant oxygen desaturation, defined as a 4% fall in oxygen saturation of hemoglobin during the 6MWD, was approximately two times greater (P less than .001) for the patients with CT evidence of emphysema.

There were no significant differences between the two groups in walking distance on the 6MWD. Both sets of patients had the same rate of exacerbations and scores on the symptom component of the St. Georges Respiratory Questionnaire, which captures cough, phlegm, wheezing, shortness of breath, and symptom-free days.

Overall, when ever smokers with preserved lung function were subdivided into those with and without CT evidence of emphysema, several similarities were found between the two groups. For those with CT evidence of emphysema and those with no CT evidence of emphysema, mean pack-years of smoking were 43 years and 40 years, respectively, and average body mass indexes were 28.1 and 29.1, respectively. The percentage of patients who had a COPD Assessment Test score of greater than or equal to 10 was 61% among those with CT evidence of emphysema, vs. 50% among those patients without CT evidence of emphysema.

When asked if looking for emphysema on CT in ever smokers with preserved lung function might have clinical utility, Dr. Lo Cascio suggested that it is not yet clear how this information might change management. These data strengthen other evidence from SPIROMICS that ever smokers who do not meet the definition of COPD already have a significant disease burden, he said.

Dr. Lo Cascio reports no relevant financial relationships.

LONDON – In patients with non–cystic fibrosis bronchiectasis (NCFB), use of inhaled ciprofloxacin on a schedule of 14 days on and 14 days off significantly reduced the rate of exacerbations, in a multicenter placebo-controlled trial. The results were presented at the annual congress of the European Respiratory Society.

“At last, an antibiotic intervention trial [in NCFB] with a positive outcome,” reported Anthony De Soyza, MBChB, PhD, senior lecturer in respiratory medicine, Newcastle (England) University. Dr. De Soyza was the study’s principal investigator.

In this study, called RESPIRE 1, the researchers conducted two placebo-controlled arms simultaneously. In one, patients randomized to inhaled ciprofloxacin or placebo took their assigned treatment twice daily for 14 days on and then 14 days off. In the other, patients took their assigned treatment of ciprofloxacin or placebo twice daily, but for 28 days on and then 28 days off. The on-off schedules were maintained for 48 weeks. The ratio of randomization of active therapy to placebo was 2:1.

There were two co-primary endpoints. One was the number of exacerbations over the 48 weeks of follow-up. Exacerbations were strictly defined as the worsening of at least three respiratory symptoms (dyspnea, wheezing, cough, increased sputum volume over 24 hours, or increased sputum purulence) plus fever with malaise or fatigue, and systemic antibiotic use. The other endpoint was the time to first exacerbation.

When the 111 patients randomized to the 14-day on-off regimen of inhaled ciprofloxacin were compared to 49 placebo patients, the mean number of exacerbations over 48 weeks of follow-up was 0.6 in the active treatment group, versus 1.0 in the placebo group (adjusted hazard ratio of 0.61, P = .0061), according to Dr. De Soyza.

The mean time to first exacerbation approached 1 year in those randomized to the 14-day on-off schedule of inhaled ciprofloxacin. In the two placebo arms (pooled for this analysis), the mean time to first exacerbation was 186 days. This difference was highly significant (HR = 0.53; P = .0005).

On the 28-day schedule, for 174 patients, there was a trend for a delay in the time to first exacerbation (HR 0.73; P = .0650) for those randomized to inhaled ciprofloxacin relative to placebo. The difference in the mean number of exacerbations between patients in the experimental group and the placebo group did not approach significance, which Dr. De Soyza said may have been caused by a lack of protection from antibiotics during the off period.

Ciprofloxacin, which was delivered in a dose of 32.5 mg in a proprietary dry powder inhalation device, was well tolerated. The overall rate of adverse events was similar across the study arms. The rates of discontinuation for adverse events in the 14-day and 28-day arms of ciprofloxacin were 12.5% and 10.6%, respectively. These rates were numerically lower than the 13.9% rate of adverse events that occurred among the patients receiving placebos.

According to previously published data cited by Dr. De Soyza, the proportion of NCFB patients with chronic lung infections is 70%, and approximately 40% of these patients have at least two exacerbations per year. In patients with at least two exacerbations per year, the 4-year mortality rate is 15%, Dr. De Soyza reported.

“There is an urgent medical need for better therapeutic strategies to improve outcome in patients with this disease,” he emphasized.

In this particular study, enrolled patients had relatively advanced NCFB. About 30% had a baseline forced expiratory volume in one second of less than 50% of predicted, about 55% had experienced two or more exacerbations in the past 12 months, 20% had been hospitalized in the last year, and more than 15% were on long-term oral macrolides, Dr. De Soyza reported.

These data will be rendered even more compelling if the similarly designed and nearly completed RESPIRE 2 trial produces similar results, he said. If both studies demonstrate protection from exacerbations, they might lead to “a paradigm shift” in the treatment of NCFB, he added.

In the context of the limited strategies currently available for NCFB, “the punch line is that this is a really exciting outcome,” he said.

Dr. De Soyza has financial relationships with AstraZeneca, Bayer, Chiesi, Forrest Labs, GlaxoSmithKline, Novartis, and Teva.

[email protected]

LONDON – In patients with non–cystic fibrosis bronchiectasis (NCFB), use of inhaled ciprofloxacin on a schedule of 14 days on and 14 days off significantly reduced the rate of exacerbations, in a multicenter placebo-controlled trial. The results were presented at the annual congress of the European Respiratory Society.

“At last, an antibiotic intervention trial [in NCFB] with a positive outcome,” reported Anthony De Soyza, MBChB, PhD, senior lecturer in respiratory medicine, Newcastle (England) University. Dr. De Soyza was the study’s principal investigator.

In this study, called RESPIRE 1, the researchers conducted two placebo-controlled arms simultaneously. In one, patients randomized to inhaled ciprofloxacin or placebo took their assigned treatment twice daily for 14 days on and then 14 days off. In the other, patients took their assigned treatment of ciprofloxacin or placebo twice daily, but for 28 days on and then 28 days off. The on-off schedules were maintained for 48 weeks. The ratio of randomization of active therapy to placebo was 2:1.

There were two co-primary endpoints. One was the number of exacerbations over the 48 weeks of follow-up. Exacerbations were strictly defined as the worsening of at least three respiratory symptoms (dyspnea, wheezing, cough, increased sputum volume over 24 hours, or increased sputum purulence) plus fever with malaise or fatigue, and systemic antibiotic use. The other endpoint was the time to first exacerbation.

When the 111 patients randomized to the 14-day on-off regimen of inhaled ciprofloxacin were compared to 49 placebo patients, the mean number of exacerbations over 48 weeks of follow-up was 0.6 in the active treatment group, versus 1.0 in the placebo group (adjusted hazard ratio of 0.61, P = .0061), according to Dr. De Soyza.

The mean time to first exacerbation approached 1 year in those randomized to the 14-day on-off schedule of inhaled ciprofloxacin. In the two placebo arms (pooled for this analysis), the mean time to first exacerbation was 186 days. This difference was highly significant (HR = 0.53; P = .0005).

On the 28-day schedule, for 174 patients, there was a trend for a delay in the time to first exacerbation (HR 0.73; P = .0650) for those randomized to inhaled ciprofloxacin relative to placebo. The difference in the mean number of exacerbations between patients in the experimental group and the placebo group did not approach significance, which Dr. De Soyza said may have been caused by a lack of protection from antibiotics during the off period.

Ciprofloxacin, which was delivered in a dose of 32.5 mg in a proprietary dry powder inhalation device, was well tolerated. The overall rate of adverse events was similar across the study arms. The rates of discontinuation for adverse events in the 14-day and 28-day arms of ciprofloxacin were 12.5% and 10.6%, respectively. These rates were numerically lower than the 13.9% rate of adverse events that occurred among the patients receiving placebos.

According to previously published data cited by Dr. De Soyza, the proportion of NCFB patients with chronic lung infections is 70%, and approximately 40% of these patients have at least two exacerbations per year. In patients with at least two exacerbations per year, the 4-year mortality rate is 15%, Dr. De Soyza reported.

“There is an urgent medical need for better therapeutic strategies to improve outcome in patients with this disease,” he emphasized.

In this particular study, enrolled patients had relatively advanced NCFB. About 30% had a baseline forced expiratory volume in one second of less than 50% of predicted, about 55% had experienced two or more exacerbations in the past 12 months, 20% had been hospitalized in the last year, and more than 15% were on long-term oral macrolides, Dr. De Soyza reported.

These data will be rendered even more compelling if the similarly designed and nearly completed RESPIRE 2 trial produces similar results, he said. If both studies demonstrate protection from exacerbations, they might lead to “a paradigm shift” in the treatment of NCFB, he added.

In the context of the limited strategies currently available for NCFB, “the punch line is that this is a really exciting outcome,” he said.

Dr. De Soyza has financial relationships with AstraZeneca, Bayer, Chiesi, Forrest Labs, GlaxoSmithKline, Novartis, and Teva.

[email protected]

LONDON – In patients with non–cystic fibrosis bronchiectasis (NCFB), use of inhaled ciprofloxacin on a schedule of 14 days on and 14 days off significantly reduced the rate of exacerbations, in a multicenter placebo-controlled trial. The results were presented at the annual congress of the European Respiratory Society.

“At last, an antibiotic intervention trial [in NCFB] with a positive outcome,” reported Anthony De Soyza, MBChB, PhD, senior lecturer in respiratory medicine, Newcastle (England) University. Dr. De Soyza was the study’s principal investigator.

In this study, called RESPIRE 1, the researchers conducted two placebo-controlled arms simultaneously. In one, patients randomized to inhaled ciprofloxacin or placebo took their assigned treatment twice daily for 14 days on and then 14 days off. In the other, patients took their assigned treatment of ciprofloxacin or placebo twice daily, but for 28 days on and then 28 days off. The on-off schedules were maintained for 48 weeks. The ratio of randomization of active therapy to placebo was 2:1.

There were two co-primary endpoints. One was the number of exacerbations over the 48 weeks of follow-up. Exacerbations were strictly defined as the worsening of at least three respiratory symptoms (dyspnea, wheezing, cough, increased sputum volume over 24 hours, or increased sputum purulence) plus fever with malaise or fatigue, and systemic antibiotic use. The other endpoint was the time to first exacerbation.

When the 111 patients randomized to the 14-day on-off regimen of inhaled ciprofloxacin were compared to 49 placebo patients, the mean number of exacerbations over 48 weeks of follow-up was 0.6 in the active treatment group, versus 1.0 in the placebo group (adjusted hazard ratio of 0.61, P = .0061), according to Dr. De Soyza.

The mean time to first exacerbation approached 1 year in those randomized to the 14-day on-off schedule of inhaled ciprofloxacin. In the two placebo arms (pooled for this analysis), the mean time to first exacerbation was 186 days. This difference was highly significant (HR = 0.53; P = .0005).

On the 28-day schedule, for 174 patients, there was a trend for a delay in the time to first exacerbation (HR 0.73; P = .0650) for those randomized to inhaled ciprofloxacin relative to placebo. The difference in the mean number of exacerbations between patients in the experimental group and the placebo group did not approach significance, which Dr. De Soyza said may have been caused by a lack of protection from antibiotics during the off period.

Ciprofloxacin, which was delivered in a dose of 32.5 mg in a proprietary dry powder inhalation device, was well tolerated. The overall rate of adverse events was similar across the study arms. The rates of discontinuation for adverse events in the 14-day and 28-day arms of ciprofloxacin were 12.5% and 10.6%, respectively. These rates were numerically lower than the 13.9% rate of adverse events that occurred among the patients receiving placebos.

According to previously published data cited by Dr. De Soyza, the proportion of NCFB patients with chronic lung infections is 70%, and approximately 40% of these patients have at least two exacerbations per year. In patients with at least two exacerbations per year, the 4-year mortality rate is 15%, Dr. De Soyza reported.

“There is an urgent medical need for better therapeutic strategies to improve outcome in patients with this disease,” he emphasized.

In this particular study, enrolled patients had relatively advanced NCFB. About 30% had a baseline forced expiratory volume in one second of less than 50% of predicted, about 55% had experienced two or more exacerbations in the past 12 months, 20% had been hospitalized in the last year, and more than 15% were on long-term oral macrolides, Dr. De Soyza reported.

These data will be rendered even more compelling if the similarly designed and nearly completed RESPIRE 2 trial produces similar results, he said. If both studies demonstrate protection from exacerbations, they might lead to “a paradigm shift” in the treatment of NCFB, he added.

In the context of the limited strategies currently available for NCFB, “the punch line is that this is a really exciting outcome,” he said.

Dr. De Soyza has financial relationships with AstraZeneca, Bayer, Chiesi, Forrest Labs, GlaxoSmithKline, Novartis, and Teva.

[email protected]

LONDON – In a proof-of-principle study, artificial intelligence (AI) led more frequently to the correct diagnosis of underlying lung disease than did physicians’ use of standard algorithms, such as those recommended by the American Thoracic Society and the European Respiratory Society, according to late-breaker data presented at the annual congress of the European Respiratory Society.

“The beauty of this approach is that artificial intelligence can simulate the complex reasoning that clinicians use to reach their diagnosis but in a more standardized and objective fashion, so it removes any bias,” reported Wim Janssens, MD, PhD, of the division of medicine and respiratory rehabilitation at University of Leuven (Belgium).

The AI employed in this study was based on a subfield of computer science that relies on patterns within statistics to build decision trees. Often called machine learning, this type of AI grows smarter as it learns from the patterns it finds in the data provided.

In this case, the AI was designed to provide diagnoses for lung diseases based on patterns drawn from clinical and lung function data. The computer-based choices were compared to diagnoses reached by clinicians. The final diagnoses were validated by a consensus of expert clinicians.

“The computer-based choices were in almost all cases better than the choices made by standard diagnostic algorithms,” reported Marko Topalovic, PhD, a researcher in AI who is affiliated with the University of Leuven. Dr. Topalovic presented the data at the ERS.

The study involved 968 patients presenting with lung symptoms to a pulmonary clinic for the first time. Standard clinical data, such as smoking history, body mass index, and age, were collected. Lung function studies conducted in all patients included spirometry, body plethysmography, and airway diffusion, although participating clinicians were permitted to order additional tests at their own discretion. Clinical diagnoses were separated into 10 predefined disease groups.

The average accuracy of clinicians’ diagnoses was 38%. The clinicians were best at identifying chronic obstructive pulmonary disease (COPD), having accurately diagnosed 74% of the cases of this disease. For other disease groups, the clinician’s accuracy rarely exceeded 50%.

The diagnoses made by AI, on the other hand, on average, were 68% accurate. For diagnosing COPD, the AI achieved a positive predictive value of 83% and a sensitivity of 78%. The positive predictive value and sensitivity of AI for asthma (66% and 82%, respectively) and interstitial lung disease (52% and 59%) were both significantly greater than those achieved by the clinicians.

When findings are ambiguous or there are anomalies in the clinical picture, a final clinical diagnosis can be challenging, according to Dr. Janssens. He suggested that automation eliminates the potential for bias, which often occurs when clinicians inadvertently give more weight to one clinical variable relative to another.

The decision-making system tested in this study was characterized as “a first step to automated interpretation of lung function,” Dr. Topalovic said. He added that he expects the AI to improve as it receives more data.

“Not only do we think this system can help nonexperienced clinicians, but it will help experts reach a diagnosis more quickly,” Dr. Topalovic said. Noting that this same approach is being pursued in other fields of medicine, he said he thinks adding AI to respiratory medicine will reduce the number of redundant tests and, in other ways, introduce opportunities for efficiencies and reduced costs.

Dr. Topalovic and Dr. Janssens reported no relevant financial relationships.

LONDON – In a proof-of-principle study, artificial intelligence (AI) led more frequently to the correct diagnosis of underlying lung disease than did physicians’ use of standard algorithms, such as those recommended by the American Thoracic Society and the European Respiratory Society, according to late-breaker data presented at the annual congress of the European Respiratory Society.

“The beauty of this approach is that artificial intelligence can simulate the complex reasoning that clinicians use to reach their diagnosis but in a more standardized and objective fashion, so it removes any bias,” reported Wim Janssens, MD, PhD, of the division of medicine and respiratory rehabilitation at University of Leuven (Belgium).

The AI employed in this study was based on a subfield of computer science that relies on patterns within statistics to build decision trees. Often called machine learning, this type of AI grows smarter as it learns from the patterns it finds in the data provided.

In this case, the AI was designed to provide diagnoses for lung diseases based on patterns drawn from clinical and lung function data. The computer-based choices were compared to diagnoses reached by clinicians. The final diagnoses were validated by a consensus of expert clinicians.

“The computer-based choices were in almost all cases better than the choices made by standard diagnostic algorithms,” reported Marko Topalovic, PhD, a researcher in AI who is affiliated with the University of Leuven. Dr. Topalovic presented the data at the ERS.

The study involved 968 patients presenting with lung symptoms to a pulmonary clinic for the first time. Standard clinical data, such as smoking history, body mass index, and age, were collected. Lung function studies conducted in all patients included spirometry, body plethysmography, and airway diffusion, although participating clinicians were permitted to order additional tests at their own discretion. Clinical diagnoses were separated into 10 predefined disease groups.

The average accuracy of clinicians’ diagnoses was 38%. The clinicians were best at identifying chronic obstructive pulmonary disease (COPD), having accurately diagnosed 74% of the cases of this disease. For other disease groups, the clinician’s accuracy rarely exceeded 50%.

The diagnoses made by AI, on the other hand, on average, were 68% accurate. For diagnosing COPD, the AI achieved a positive predictive value of 83% and a sensitivity of 78%. The positive predictive value and sensitivity of AI for asthma (66% and 82%, respectively) and interstitial lung disease (52% and 59%) were both significantly greater than those achieved by the clinicians.

When findings are ambiguous or there are anomalies in the clinical picture, a final clinical diagnosis can be challenging, according to Dr. Janssens. He suggested that automation eliminates the potential for bias, which often occurs when clinicians inadvertently give more weight to one clinical variable relative to another.

The decision-making system tested in this study was characterized as “a first step to automated interpretation of lung function,” Dr. Topalovic said. He added that he expects the AI to improve as it receives more data.

“Not only do we think this system can help nonexperienced clinicians, but it will help experts reach a diagnosis more quickly,” Dr. Topalovic said. Noting that this same approach is being pursued in other fields of medicine, he said he thinks adding AI to respiratory medicine will reduce the number of redundant tests and, in other ways, introduce opportunities for efficiencies and reduced costs.

Dr. Topalovic and Dr. Janssens reported no relevant financial relationships.

LONDON – In a proof-of-principle study, artificial intelligence (AI) led more frequently to the correct diagnosis of underlying lung disease than did physicians’ use of standard algorithms, such as those recommended by the American Thoracic Society and the European Respiratory Society, according to late-breaker data presented at the annual congress of the European Respiratory Society.

“The beauty of this approach is that artificial intelligence can simulate the complex reasoning that clinicians use to reach their diagnosis but in a more standardized and objective fashion, so it removes any bias,” reported Wim Janssens, MD, PhD, of the division of medicine and respiratory rehabilitation at University of Leuven (Belgium).

The AI employed in this study was based on a subfield of computer science that relies on patterns within statistics to build decision trees. Often called machine learning, this type of AI grows smarter as it learns from the patterns it finds in the data provided.

In this case, the AI was designed to provide diagnoses for lung diseases based on patterns drawn from clinical and lung function data. The computer-based choices were compared to diagnoses reached by clinicians. The final diagnoses were validated by a consensus of expert clinicians.

“The computer-based choices were in almost all cases better than the choices made by standard diagnostic algorithms,” reported Marko Topalovic, PhD, a researcher in AI who is affiliated with the University of Leuven. Dr. Topalovic presented the data at the ERS.

The study involved 968 patients presenting with lung symptoms to a pulmonary clinic for the first time. Standard clinical data, such as smoking history, body mass index, and age, were collected. Lung function studies conducted in all patients included spirometry, body plethysmography, and airway diffusion, although participating clinicians were permitted to order additional tests at their own discretion. Clinical diagnoses were separated into 10 predefined disease groups.

The average accuracy of clinicians’ diagnoses was 38%. The clinicians were best at identifying chronic obstructive pulmonary disease (COPD), having accurately diagnosed 74% of the cases of this disease. For other disease groups, the clinician’s accuracy rarely exceeded 50%.

The diagnoses made by AI, on the other hand, on average, were 68% accurate. For diagnosing COPD, the AI achieved a positive predictive value of 83% and a sensitivity of 78%. The positive predictive value and sensitivity of AI for asthma (66% and 82%, respectively) and interstitial lung disease (52% and 59%) were both significantly greater than those achieved by the clinicians.

When findings are ambiguous or there are anomalies in the clinical picture, a final clinical diagnosis can be challenging, according to Dr. Janssens. He suggested that automation eliminates the potential for bias, which often occurs when clinicians inadvertently give more weight to one clinical variable relative to another.

The decision-making system tested in this study was characterized as “a first step to automated interpretation of lung function,” Dr. Topalovic said. He added that he expects the AI to improve as it receives more data.

“Not only do we think this system can help nonexperienced clinicians, but it will help experts reach a diagnosis more quickly,” Dr. Topalovic said. Noting that this same approach is being pursued in other fields of medicine, he said he thinks adding AI to respiratory medicine will reduce the number of redundant tests and, in other ways, introduce opportunities for efficiencies and reduced costs.

Dr. Topalovic and Dr. Janssens reported no relevant financial relationships.

LONDON – A study comparing patient data with six definitions of the Asthma-COPD Overlap Syndrome (ACOS) found only one of the patients analyzed met all definitions. This provoked an animated discussion at the annual congress of the European Respiratory Society about the utility of ACOS as a clinical entity.

Of 864 patients diagnosed with chronic obstructive pulmonary disease (COPD) or asthma drawn from the Netherlands Epidemiology of Obesity cohort (a population-based study with 5,784 patients), 39.1% (338 patients) met at least one of the definitions of ACOS, while 0.1% (one patient) met the criteria for all six definitions.

When this finding was presented, the ERS audience first laughed and then applauded. At the end of the presentation, long lines formed at the microphones. Every comment made was hostile to the concept of ACOS.

“Let us bring ACOS to an honorable death,” said one audience member. His point, reiterated by all who commented subsequently, was that ACOS confuses efforts to treat the underlying respiratory symptoms. Even in those who have both asthma and COPD, the speaker, like other members of the audience, said he considered the diagnosis of ACOS unhelpful.

The six definitions in the study included the latest and just published consensus definition from the ERS (Eur Respir J. 2016;48[3]:664-73). According to the ERS definition, the key features of ACOS are age greater than 40 years, long-term history of asthma (since childhood or early adulthood), and significant exposure to cigarette or biomass smoke.

The other definitions analyzed included a medical history of both asthma and COPD, a self-reported history of both asthma and COPD, and a record of the proportion of a person’s vital capacity that he/she is able to expire in 1 second of forced expiration of less than 0.7 plus a record of fractionated nitric oxide concentration in exhaled breath of greater than or equal to 45 parts per billion.

Although attempted, a Venn diagram that would show overlapping subsets of patients that fell into these definitions “was not possible,” according to Tobias Bonten, MD, University of Leiden, the Netherlands.

Asthma duration was just over 10 years in those identified as having ACOS by medical history alone (registry-based definitions), just over 20 years in those with a medical history and objective evidence of impaired lung function, but about 40 years in those with a self-report of both asthma and COPD.

One area that all groups created by the ACOS definitions did have in common was demographic variables, such as median age, proportion of patients defined as overweight or obese by body mass index, and proportion who were current smokers.

Members of the audience acknowledged the importance of considering the coexistence of asthma and COPD, but expressed skepticism about the value of ACOS as a separate entity in the clinic.

“ACOS is something like the emperor’s new clothes,” one audience member said during the discussion. “It is important to identify asthma patients with obstruction because they have reduced lung function that should be treated more actively, but I find the definition [of ACOS] unnecessary,” he said.

A similar conclusion was drawn in a review article devoted to ACOS published last year (N Engl J Med. 2015;373[13]:1241-9). “It is premature to recommend the designation of ACOS as a disease entity,” the authors wrote.

This is a position widely shared by clinicians, judging from audience comments provoked by this demonstration.

For the sake of time, the moderators were forced to end the discussion with significant lines of clinicians at the microphone.

“It is quite clear that ACOS should die,” said one of the last speakers given a chance to voice an opinion. He suggested that the coexistence of asthma and COPD is something that “quite clearly can happen,” but he objected to definitions he said are unhelpful for clinical care.

Dr. Bonten reported no relevant financial relationships.

LONDON – A study comparing patient data with six definitions of the Asthma-COPD Overlap Syndrome (ACOS) found only one of the patients analyzed met all definitions. This provoked an animated discussion at the annual congress of the European Respiratory Society about the utility of ACOS as a clinical entity.

Of 864 patients diagnosed with chronic obstructive pulmonary disease (COPD) or asthma drawn from the Netherlands Epidemiology of Obesity cohort (a population-based study with 5,784 patients), 39.1% (338 patients) met at least one of the definitions of ACOS, while 0.1% (one patient) met the criteria for all six definitions.

When this finding was presented, the ERS audience first laughed and then applauded. At the end of the presentation, long lines formed at the microphones. Every comment made was hostile to the concept of ACOS.

“Let us bring ACOS to an honorable death,” said one audience member. His point, reiterated by all who commented subsequently, was that ACOS confuses efforts to treat the underlying respiratory symptoms. Even in those who have both asthma and COPD, the speaker, like other members of the audience, said he considered the diagnosis of ACOS unhelpful.

The six definitions in the study included the latest and just published consensus definition from the ERS (Eur Respir J. 2016;48[3]:664-73). According to the ERS definition, the key features of ACOS are age greater than 40 years, long-term history of asthma (since childhood or early adulthood), and significant exposure to cigarette or biomass smoke.

The other definitions analyzed included a medical history of both asthma and COPD, a self-reported history of both asthma and COPD, and a record of the proportion of a person’s vital capacity that he/she is able to expire in 1 second of forced expiration of less than 0.7 plus a record of fractionated nitric oxide concentration in exhaled breath of greater than or equal to 45 parts per billion.

Although attempted, a Venn diagram that would show overlapping subsets of patients that fell into these definitions “was not possible,” according to Tobias Bonten, MD, University of Leiden, the Netherlands.

Asthma duration was just over 10 years in those identified as having ACOS by medical history alone (registry-based definitions), just over 20 years in those with a medical history and objective evidence of impaired lung function, but about 40 years in those with a self-report of both asthma and COPD.

One area that all groups created by the ACOS definitions did have in common was demographic variables, such as median age, proportion of patients defined as overweight or obese by body mass index, and proportion who were current smokers.

Members of the audience acknowledged the importance of considering the coexistence of asthma and COPD, but expressed skepticism about the value of ACOS as a separate entity in the clinic.

“ACOS is something like the emperor’s new clothes,” one audience member said during the discussion. “It is important to identify asthma patients with obstruction because they have reduced lung function that should be treated more actively, but I find the definition [of ACOS] unnecessary,” he said.

A similar conclusion was drawn in a review article devoted to ACOS published last year (N Engl J Med. 2015;373[13]:1241-9). “It is premature to recommend the designation of ACOS as a disease entity,” the authors wrote.

This is a position widely shared by clinicians, judging from audience comments provoked by this demonstration.

For the sake of time, the moderators were forced to end the discussion with significant lines of clinicians at the microphone.

“It is quite clear that ACOS should die,” said one of the last speakers given a chance to voice an opinion. He suggested that the coexistence of asthma and COPD is something that “quite clearly can happen,” but he objected to definitions he said are unhelpful for clinical care.

Dr. Bonten reported no relevant financial relationships.

LONDON – A study comparing patient data with six definitions of the Asthma-COPD Overlap Syndrome (ACOS) found only one of the patients analyzed met all definitions. This provoked an animated discussion at the annual congress of the European Respiratory Society about the utility of ACOS as a clinical entity.

Of 864 patients diagnosed with chronic obstructive pulmonary disease (COPD) or asthma drawn from the Netherlands Epidemiology of Obesity cohort (a population-based study with 5,784 patients), 39.1% (338 patients) met at least one of the definitions of ACOS, while 0.1% (one patient) met the criteria for all six definitions.

When this finding was presented, the ERS audience first laughed and then applauded. At the end of the presentation, long lines formed at the microphones. Every comment made was hostile to the concept of ACOS.

“Let us bring ACOS to an honorable death,” said one audience member. His point, reiterated by all who commented subsequently, was that ACOS confuses efforts to treat the underlying respiratory symptoms. Even in those who have both asthma and COPD, the speaker, like other members of the audience, said he considered the diagnosis of ACOS unhelpful.

The six definitions in the study included the latest and just published consensus definition from the ERS (Eur Respir J. 2016;48[3]:664-73). According to the ERS definition, the key features of ACOS are age greater than 40 years, long-term history of asthma (since childhood or early adulthood), and significant exposure to cigarette or biomass smoke.

The other definitions analyzed included a medical history of both asthma and COPD, a self-reported history of both asthma and COPD, and a record of the proportion of a person’s vital capacity that he/she is able to expire in 1 second of forced expiration of less than 0.7 plus a record of fractionated nitric oxide concentration in exhaled breath of greater than or equal to 45 parts per billion.

Although attempted, a Venn diagram that would show overlapping subsets of patients that fell into these definitions “was not possible,” according to Tobias Bonten, MD, University of Leiden, the Netherlands.

Asthma duration was just over 10 years in those identified as having ACOS by medical history alone (registry-based definitions), just over 20 years in those with a medical history and objective evidence of impaired lung function, but about 40 years in those with a self-report of both asthma and COPD.

One area that all groups created by the ACOS definitions did have in common was demographic variables, such as median age, proportion of patients defined as overweight or obese by body mass index, and proportion who were current smokers.

Members of the audience acknowledged the importance of considering the coexistence of asthma and COPD, but expressed skepticism about the value of ACOS as a separate entity in the clinic.

“ACOS is something like the emperor’s new clothes,” one audience member said during the discussion. “It is important to identify asthma patients with obstruction because they have reduced lung function that should be treated more actively, but I find the definition [of ACOS] unnecessary,” he said.

A similar conclusion was drawn in a review article devoted to ACOS published last year (N Engl J Med. 2015;373[13]:1241-9). “It is premature to recommend the designation of ACOS as a disease entity,” the authors wrote.

This is a position widely shared by clinicians, judging from audience comments provoked by this demonstration.

For the sake of time, the moderators were forced to end the discussion with significant lines of clinicians at the microphone.

“It is quite clear that ACOS should die,” said one of the last speakers given a chance to voice an opinion. He suggested that the coexistence of asthma and COPD is something that “quite clearly can happen,” but he objected to definitions he said are unhelpful for clinical care.

Dr. Bonten reported no relevant financial relationships.

LONDON – Based on readily available clinical data, patients with chronic obstructive pulmonary disease (COPD) can be placed into five phenotypes with different characteristics and risk profiles, according to data generated by a cluster analysis and presented at the European Respiratory Society International Congress 2016.

The algorithm that places patients into these phenotypes was developed from a cluster analysis, reported Pierre-Regis Burgel, MD, PhD, professor of respiratory medicine, Université Réné Descartes, Paris. Mortality rates at 3 years for these phenotypes ranged from 2.6% to 49.5%

“We think that this could be the basis for recognizing clinically distinct COPD phenotypes and designing better tailored management,” Dr. Burgel explained. “We also think it has potential use in routine clinical assessment.”

To create these phenotypes, data from 2,049 COPD patients enrolled in a French-Belgian collaborative cohort were evaluated with Classification And Regression Tree (CART) analyses. The five phenotypes were derived from symptom burden, respiratory function, relative age, and presence of comorbidities.

Based on these characteristics, “a set of clinical rules” to phenotype patients was developed, according to Dr. Burgel. This algorithm was then further validated with the 3,651 COPD patients enrolled in the prospective COPD Cohorts Collaborative International Assessment (3CIA) initiative.

The two initial branches in the algorithm are created by dividing patients into those with and without cardiovascular comorbidities or diabetes. In those without cardiovascular disease, the phenotypes are defined by relative symptom severity, using cut-off scores from the modified Medical Research Council (mMRC) dyspnea assessment tool and relative degrees of lung function impairment as measured with forced expiratory volume in 1 second (FEV₁).

In those with cardiovascular disease or diabetes, mMRC-defined symptoms and FEV₁-defined lung function impairment also create decision points in the algorithm, but age and body mass index (BMI) are additional variables that direct patients to a specific phenotype. Class 4 and 5 are reached in the absence of cardiovascular disease or diabetes only, while cardiovascular disease is a prerequisite to reach Classes 4 and 5. Class 2 is the only phenotype that can be reached through the algorithm irrespective of the presence or absence of cardiovascular disease.

Using this algorithm, each of the phenotypes was associated with similar relative hierarchy in mortality in the two cohorts, even though mortality rates for each phenotype were consistently lower in the 3CIA group.

For class 1, which was reached by patients with cardiovascular disease or diabetes, the greatest symptom burden, and the lowest lung function, the mortality rates at 3 years were 49.5% and 23.2% for the French-Belgian and 3CIA cohorts, respectively.

For class 4, which was also defined by the greatest symptom burden and the lowest lung function without cardiovascular disease or diabetes the mortality rates were 45.3% and 27.3%, respectively. The lowest mortality rates, which were 2.6% and 4.0%, respectively, were found in the class 5 phenotype, which contained patients with a low symptom burden (mMRC less than or equal to 1), relatively good lung function (FEV₁ greater than or equal to 60%), and no history of cardiovascular disease or diabetes.

In classes 2 and 3, the mortality rates fell in between those of the lowest- and highest-risk phenotypes. Specifically, these 3-year mortality rates were 22.9% and 24%, respectively, in the French-Belgian cohort, and 11.1% and 14.1%, respectively, in the 3CIA cohort.

The consistency of the hierarchy of outcomes in the two cohorts provides the basis for suggesting that these phenotypes are effective for categorizing relative risk, according to Dr. Burgel. He believes that the phenotypes are clinically important, and he emphasized that the algorithm relies on clinical information that is already routinely collected and readily accessible.

“There is growing awareness that COPD phenotypes are important and are likely to be valuable in managing patients,” Dr. Burgel explained. “We feel that we have created simple rules for allocating patients that we think will be useful for research and for clinical application.”

Dr. Burgel reported financial relationships with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer, and Vertex.

LONDON – Based on readily available clinical data, patients with chronic obstructive pulmonary disease (COPD) can be placed into five phenotypes with different characteristics and risk profiles, according to data generated by a cluster analysis and presented at the European Respiratory Society International Congress 2016.

The algorithm that places patients into these phenotypes was developed from a cluster analysis, reported Pierre-Regis Burgel, MD, PhD, professor of respiratory medicine, Université Réné Descartes, Paris. Mortality rates at 3 years for these phenotypes ranged from 2.6% to 49.5%

“We think that this could be the basis for recognizing clinically distinct COPD phenotypes and designing better tailored management,” Dr. Burgel explained. “We also think it has potential use in routine clinical assessment.”

To create these phenotypes, data from 2,049 COPD patients enrolled in a French-Belgian collaborative cohort were evaluated with Classification And Regression Tree (CART) analyses. The five phenotypes were derived from symptom burden, respiratory function, relative age, and presence of comorbidities.

Based on these characteristics, “a set of clinical rules” to phenotype patients was developed, according to Dr. Burgel. This algorithm was then further validated with the 3,651 COPD patients enrolled in the prospective COPD Cohorts Collaborative International Assessment (3CIA) initiative.

The two initial branches in the algorithm are created by dividing patients into those with and without cardiovascular comorbidities or diabetes. In those without cardiovascular disease, the phenotypes are defined by relative symptom severity, using cut-off scores from the modified Medical Research Council (mMRC) dyspnea assessment tool and relative degrees of lung function impairment as measured with forced expiratory volume in 1 second (FEV₁).

In those with cardiovascular disease or diabetes, mMRC-defined symptoms and FEV₁-defined lung function impairment also create decision points in the algorithm, but age and body mass index (BMI) are additional variables that direct patients to a specific phenotype. Class 4 and 5 are reached in the absence of cardiovascular disease or diabetes only, while cardiovascular disease is a prerequisite to reach Classes 4 and 5. Class 2 is the only phenotype that can be reached through the algorithm irrespective of the presence or absence of cardiovascular disease.

Using this algorithm, each of the phenotypes was associated with similar relative hierarchy in mortality in the two cohorts, even though mortality rates for each phenotype were consistently lower in the 3CIA group.

For class 1, which was reached by patients with cardiovascular disease or diabetes, the greatest symptom burden, and the lowest lung function, the mortality rates at 3 years were 49.5% and 23.2% for the French-Belgian and 3CIA cohorts, respectively.

For class 4, which was also defined by the greatest symptom burden and the lowest lung function without cardiovascular disease or diabetes the mortality rates were 45.3% and 27.3%, respectively. The lowest mortality rates, which were 2.6% and 4.0%, respectively, were found in the class 5 phenotype, which contained patients with a low symptom burden (mMRC less than or equal to 1), relatively good lung function (FEV₁ greater than or equal to 60%), and no history of cardiovascular disease or diabetes.

In classes 2 and 3, the mortality rates fell in between those of the lowest- and highest-risk phenotypes. Specifically, these 3-year mortality rates were 22.9% and 24%, respectively, in the French-Belgian cohort, and 11.1% and 14.1%, respectively, in the 3CIA cohort.

The consistency of the hierarchy of outcomes in the two cohorts provides the basis for suggesting that these phenotypes are effective for categorizing relative risk, according to Dr. Burgel. He believes that the phenotypes are clinically important, and he emphasized that the algorithm relies on clinical information that is already routinely collected and readily accessible.

“There is growing awareness that COPD phenotypes are important and are likely to be valuable in managing patients,” Dr. Burgel explained. “We feel that we have created simple rules for allocating patients that we think will be useful for research and for clinical application.”

Dr. Burgel reported financial relationships with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer, and Vertex.

LONDON – Based on readily available clinical data, patients with chronic obstructive pulmonary disease (COPD) can be placed into five phenotypes with different characteristics and risk profiles, according to data generated by a cluster analysis and presented at the European Respiratory Society International Congress 2016.

The algorithm that places patients into these phenotypes was developed from a cluster analysis, reported Pierre-Regis Burgel, MD, PhD, professor of respiratory medicine, Université Réné Descartes, Paris. Mortality rates at 3 years for these phenotypes ranged from 2.6% to 49.5%

“We think that this could be the basis for recognizing clinically distinct COPD phenotypes and designing better tailored management,” Dr. Burgel explained. “We also think it has potential use in routine clinical assessment.”

To create these phenotypes, data from 2,049 COPD patients enrolled in a French-Belgian collaborative cohort were evaluated with Classification And Regression Tree (CART) analyses. The five phenotypes were derived from symptom burden, respiratory function, relative age, and presence of comorbidities.

Based on these characteristics, “a set of clinical rules” to phenotype patients was developed, according to Dr. Burgel. This algorithm was then further validated with the 3,651 COPD patients enrolled in the prospective COPD Cohorts Collaborative International Assessment (3CIA) initiative.

The two initial branches in the algorithm are created by dividing patients into those with and without cardiovascular comorbidities or diabetes. In those without cardiovascular disease, the phenotypes are defined by relative symptom severity, using cut-off scores from the modified Medical Research Council (mMRC) dyspnea assessment tool and relative degrees of lung function impairment as measured with forced expiratory volume in 1 second (FEV₁).

In those with cardiovascular disease or diabetes, mMRC-defined symptoms and FEV₁-defined lung function impairment also create decision points in the algorithm, but age and body mass index (BMI) are additional variables that direct patients to a specific phenotype. Class 4 and 5 are reached in the absence of cardiovascular disease or diabetes only, while cardiovascular disease is a prerequisite to reach Classes 4 and 5. Class 2 is the only phenotype that can be reached through the algorithm irrespective of the presence or absence of cardiovascular disease.

Using this algorithm, each of the phenotypes was associated with similar relative hierarchy in mortality in the two cohorts, even though mortality rates for each phenotype were consistently lower in the 3CIA group.

For class 1, which was reached by patients with cardiovascular disease or diabetes, the greatest symptom burden, and the lowest lung function, the mortality rates at 3 years were 49.5% and 23.2% for the French-Belgian and 3CIA cohorts, respectively.

For class 4, which was also defined by the greatest symptom burden and the lowest lung function without cardiovascular disease or diabetes the mortality rates were 45.3% and 27.3%, respectively. The lowest mortality rates, which were 2.6% and 4.0%, respectively, were found in the class 5 phenotype, which contained patients with a low symptom burden (mMRC less than or equal to 1), relatively good lung function (FEV₁ greater than or equal to 60%), and no history of cardiovascular disease or diabetes.

In classes 2 and 3, the mortality rates fell in between those of the lowest- and highest-risk phenotypes. Specifically, these 3-year mortality rates were 22.9% and 24%, respectively, in the French-Belgian cohort, and 11.1% and 14.1%, respectively, in the 3CIA cohort.

The consistency of the hierarchy of outcomes in the two cohorts provides the basis for suggesting that these phenotypes are effective for categorizing relative risk, according to Dr. Burgel. He believes that the phenotypes are clinically important, and he emphasized that the algorithm relies on clinical information that is already routinely collected and readily accessible.

“There is growing awareness that COPD phenotypes are important and are likely to be valuable in managing patients,” Dr. Burgel explained. “We feel that we have created simple rules for allocating patients that we think will be useful for research and for clinical application.”

Dr. Burgel reported financial relationships with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer, and Vertex.

LONDON – A cytokine known as tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is showing potential as a biomarker for evaluating the severity of sepsis and septic shock, according to results of a prospective study presented at the annual congress of the European Respiratory Society.

In a prospective study undertaken in patients administered to an intensive care unit, “lower levels of plasma TRAIL correlated with both organ system dysfunction and mortality,” reported Thomas Nicholson, MD, of Cornell University, New York.

A series of studies associating low levels of TRAIL with increased sepsis severity have attracted attention to this potential biomarker, according to Dr. Nicholson. In a mouse model of sepsis, for example, exogenous administration of TRAIL was associated with improved survival. In a clinical study conducted in CHINA that was cited by Dr. Nicholson, low levels of TRAIL correlated with lower rates of survival.

In the data presented at the ERS Congress, plasma TRAIL was collected from 108 patients on the first day of ICU admission. Of these patients 59 (54%) had sepsis and 23 (21%) had septic shock. Those with a noninfectious critical illness served as controls.

All patients with sepsis or septic shock were required to meet diagnostic criteria from the recently published Third International Consensus Definitions for Sepsis and Septic Shock (JAMA. 2016;315[8]:801-10). This is important because the newer criteria, relative to previous criteria, have “moved conceptually away from a condition defined by inflammatory biomarkers toward one that emphasizes signs of organ dysfunction,” Dr. Nicholson reported.

Although a dysregulated host response to infection is still a fundamental concept to the newer definition of sepsis, the importance of biomarkers of inflammation has been deemphasized, a change that would not be expected to favor an inflammatory cytokine as a biomarker.

Despite this, plasma TRAIL levels, which were measured with commercially available ELISA kits, were significantly lower for those with sepsis (P = .038) and for those with septic shock (P less than .001) relative to those with a noninfectious critical illness. There was a trend (P = .077) for lower plasma levels of TRAIL in patients with septic shock relative to sepsis.

In addition, there was a positive and significant correlation (r = –0.1983; P = .0397) between plasma TRAIL and degree of organ dysfunction as measured with the Sequential Organ Failure Assessment (SOFA) score. Higher plasma TRAIL levels also predicted survival at 28 days (P = .016). Although the overall mortality for patients with sepsis or septic shock in this series was 23%, there were no deaths among sepsis or septic shock patients with a TRAIL above the mean, which was 26.8 pg/mL.

“For every 10 mg/mL increase in TRAIL the odds ratio for survival increased by 1.9-fold,” Dr. Nicholson reported.

TRAIL is implicated in several processes that may explain these observations, according to Dr. Nicholson. For example, he reported that there is evidence that TRAIL induces apoptosis in neutrophils, a suspected mediator of sepsis-related injury.

“The observations in our study are consistent with a growing literature suggesting that TRAIL is an important mediator of inflammatory cells, such as neutrophils, tempering the degree of inflammation,” Dr. Nicholson explained.

More data are needed to verify that TRAIL is a clinically useful biomarker, but Dr. Nicholson emphasized that this is a promising area of research. He said the biomarker is being developed as a potential tool for evaluating sepsis severity.

Dr. Nicholson reported no relevant financial relationships.

LONDON – A cytokine known as tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is showing potential as a biomarker for evaluating the severity of sepsis and septic shock, according to results of a prospective study presented at the annual congress of the European Respiratory Society.

In a prospective study undertaken in patients administered to an intensive care unit, “lower levels of plasma TRAIL correlated with both organ system dysfunction and mortality,” reported Thomas Nicholson, MD, of Cornell University, New York.

A series of studies associating low levels of TRAIL with increased sepsis severity have attracted attention to this potential biomarker, according to Dr. Nicholson. In a mouse model of sepsis, for example, exogenous administration of TRAIL was associated with improved survival. In a clinical study conducted in CHINA that was cited by Dr. Nicholson, low levels of TRAIL correlated with lower rates of survival.

In the data presented at the ERS Congress, plasma TRAIL was collected from 108 patients on the first day of ICU admission. Of these patients 59 (54%) had sepsis and 23 (21%) had septic shock. Those with a noninfectious critical illness served as controls.

All patients with sepsis or septic shock were required to meet diagnostic criteria from the recently published Third International Consensus Definitions for Sepsis and Septic Shock (JAMA. 2016;315[8]:801-10). This is important because the newer criteria, relative to previous criteria, have “moved conceptually away from a condition defined by inflammatory biomarkers toward one that emphasizes signs of organ dysfunction,” Dr. Nicholson reported.

Although a dysregulated host response to infection is still a fundamental concept to the newer definition of sepsis, the importance of biomarkers of inflammation has been deemphasized, a change that would not be expected to favor an inflammatory cytokine as a biomarker.

Despite this, plasma TRAIL levels, which were measured with commercially available ELISA kits, were significantly lower for those with sepsis (P = .038) and for those with septic shock (P less than .001) relative to those with a noninfectious critical illness. There was a trend (P = .077) for lower plasma levels of TRAIL in patients with septic shock relative to sepsis.

In addition, there was a positive and significant correlation (r = –0.1983; P = .0397) between plasma TRAIL and degree of organ dysfunction as measured with the Sequential Organ Failure Assessment (SOFA) score. Higher plasma TRAIL levels also predicted survival at 28 days (P = .016). Although the overall mortality for patients with sepsis or septic shock in this series was 23%, there were no deaths among sepsis or septic shock patients with a TRAIL above the mean, which was 26.8 pg/mL.

“For every 10 mg/mL increase in TRAIL the odds ratio for survival increased by 1.9-fold,” Dr. Nicholson reported.

TRAIL is implicated in several processes that may explain these observations, according to Dr. Nicholson. For example, he reported that there is evidence that TRAIL induces apoptosis in neutrophils, a suspected mediator of sepsis-related injury.

“The observations in our study are consistent with a growing literature suggesting that TRAIL is an important mediator of inflammatory cells, such as neutrophils, tempering the degree of inflammation,” Dr. Nicholson explained.

More data are needed to verify that TRAIL is a clinically useful biomarker, but Dr. Nicholson emphasized that this is a promising area of research. He said the biomarker is being developed as a potential tool for evaluating sepsis severity.

Dr. Nicholson reported no relevant financial relationships.

LONDON – A cytokine known as tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is showing potential as a biomarker for evaluating the severity of sepsis and septic shock, according to results of a prospective study presented at the annual congress of the European Respiratory Society.

In a prospective study undertaken in patients administered to an intensive care unit, “lower levels of plasma TRAIL correlated with both organ system dysfunction and mortality,” reported Thomas Nicholson, MD, of Cornell University, New York.

A series of studies associating low levels of TRAIL with increased sepsis severity have attracted attention to this potential biomarker, according to Dr. Nicholson. In a mouse model of sepsis, for example, exogenous administration of TRAIL was associated with improved survival. In a clinical study conducted in CHINA that was cited by Dr. Nicholson, low levels of TRAIL correlated with lower rates of survival.

In the data presented at the ERS Congress, plasma TRAIL was collected from 108 patients on the first day of ICU admission. Of these patients 59 (54%) had sepsis and 23 (21%) had septic shock. Those with a noninfectious critical illness served as controls.

All patients with sepsis or septic shock were required to meet diagnostic criteria from the recently published Third International Consensus Definitions for Sepsis and Septic Shock (JAMA. 2016;315[8]:801-10). This is important because the newer criteria, relative to previous criteria, have “moved conceptually away from a condition defined by inflammatory biomarkers toward one that emphasizes signs of organ dysfunction,” Dr. Nicholson reported.

Although a dysregulated host response to infection is still a fundamental concept to the newer definition of sepsis, the importance of biomarkers of inflammation has been deemphasized, a change that would not be expected to favor an inflammatory cytokine as a biomarker.

Despite this, plasma TRAIL levels, which were measured with commercially available ELISA kits, were significantly lower for those with sepsis (P = .038) and for those with septic shock (P less than .001) relative to those with a noninfectious critical illness. There was a trend (P = .077) for lower plasma levels of TRAIL in patients with septic shock relative to sepsis.

In addition, there was a positive and significant correlation (r = –0.1983; P = .0397) between plasma TRAIL and degree of organ dysfunction as measured with the Sequential Organ Failure Assessment (SOFA) score. Higher plasma TRAIL levels also predicted survival at 28 days (P = .016). Although the overall mortality for patients with sepsis or septic shock in this series was 23%, there were no deaths among sepsis or septic shock patients with a TRAIL above the mean, which was 26.8 pg/mL.

“For every 10 mg/mL increase in TRAIL the odds ratio for survival increased by 1.9-fold,” Dr. Nicholson reported.

TRAIL is implicated in several processes that may explain these observations, according to Dr. Nicholson. For example, he reported that there is evidence that TRAIL induces apoptosis in neutrophils, a suspected mediator of sepsis-related injury.

“The observations in our study are consistent with a growing literature suggesting that TRAIL is an important mediator of inflammatory cells, such as neutrophils, tempering the degree of inflammation,” Dr. Nicholson explained.

More data are needed to verify that TRAIL is a clinically useful biomarker, but Dr. Nicholson emphasized that this is a promising area of research. He said the biomarker is being developed as a potential tool for evaluating sepsis severity.

Dr. Nicholson reported no relevant financial relationships.

LONDON – In chronic obstructive pulmonary disease (COPD), the advantage of a long-acting beta agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) over a LABA plus an inhaled corticosteroid (ICS) was observed in every subgroup in the FLAME trial evaluated, according to post hoc analyses presented at the annual congress of the European Respiratory Society.

“We thought that we might not see the difference in the COPD patients with more severe disease, but the advantage was consistent even among those who entered the trial on triple therapy,” reported Jadwiga A. Wedzicha, MD, professor of respiratory medicine at the National Heart and Lung Institute, Imperial College, London.

FLAME, the recently published study that compared LABA/LAMA to LABA/ICS, was planned as a noninferiority study with the underlying hypothesis that LABA/LAMA would perform as well as LABA/ICS for the primary outcome of annual rate of COPD exacerbations (N Engl J Med. 2016;374:2222-34). Instead, the 11% lower rate of exacerbations for LABA/LAMA proved statistically significant (P = .003).

Six post hoc FLAME analyses were presented at the 2016 ERS Congress to further explore this result. All supported the main result. In addition to evaluating those who entered the trial on a LABA/LAMA/ICS triple-therapy combination, the analyses covered a broad array of subgroups defined by age, smoking history, and COPD severity as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifications.

In FLAME, 3,362 COPD patients who had at least one exacerbation in the preceding year were randomized to the LABA indacaterol (110 mcg) plus the LAMA glycopyrronium (50 mcg) once daily or the combination of the LABA salmeterol (50 mcg) and the ICS fluticasone (500 mcg) twice daily. In addition to the relative advantage on the primary outcome of any exacerbation, the LABA/LAMA combination also significantly reduced the rate of moderate to severe exacerbations (P less than .001), and it extended the times to the first moderate to severe exacerbation (P less than .001) and the first severe exacerbation (P = .046), according to the published data.

In the post hoc analyses, the advantage of LABA/LAMA relative to LAMA/ICS was remarkably consistent. For example, in stratifications made for age (less than 55 years, 55 to less than 65 years, 65-75 years, and greater than or equal to 75 years) at least a numerical advantage of LABA/LAMA was seen in all age groups for prevention of any exacerbation, and the difference reached statistical significance for those in the age group 55 to greater than 65 years. For prevention of moderate to severe exacerbations, the treatments were found to be equivalent for individuals younger than 55 years, but LABA/LAMA was statistically superior for the other three age categories.

For ex-smokers, unlike current smokers, the numerical advantage of LABA/LAMA over LABA/ICS for reduction in the rate ratio of all exacerbations did not reach statistical significance, but the LABA/LAMA combination did provide a statistically significant advantage for both ex-smokers and current smokers for moderate to severe exacerbations.

For patients with two or more exacerbations in the year prior to enrollment in FLAME, the relative degree of protection was of magnitude similar to that of patients with only one exacerbation even though the relative advantage in those with multiple prior exacerbations did not reach statistical significance. However, the lack of significance was likely due to the relatively small number of patients in this subpopulation, according to Dr. Wedzicha.

Similarly, the LABA/LAMA combination was at least numerically superior to LABA/ICS for all exacerbations and for moderate to severe exacerbations across GOLD classifications with one exception. When compared for relative protection against moderate to severe exacerbations, there was a slight and nonsignificant disadvantage for LABA/LAMA, but, again, Dr. Wedzicha reported, “the number of patients in this subgroup was quite small.”

In another FLAME post hoc analysis, the odds ratio (OR) for exacerbations among the 1,893 patients (56.3%) who were on ICS at study entry was found to be almost identical to the OR among those who were not. Specifically, the ORs for all exacerbations and moderate to severe exacerbations were 0.88 (P = .008) and 0.86 (P = .018), respectively, for those previously treated with ICS and 0.88 (P = .021) and 0.78 (P = .002), respectively, for those who had not been treated with ICS.

The LABA/LAMA combination was also superior to LABA/ICS for improvements in quality of life, which was measured via the St. George’s Respiratory Questionnaire. With an improvement of at least four units on the St. George’s Respiratory Questionnaire defined as clinically meaningful, 49.5% of LABA/LAMA patients versus 43.8% of LABA/ICS patients (P less than .024) benefited on this measure.

Overall, the results from the FLAME post hoc analyses have demonstrated “remarkable consistency,” Dr. Wedzicha reported. Taken together, she said the data “imply that LABA/LAMA is the first choice of treatment for COPD patients at risk of exacerbation.”

LONDON – In chronic obstructive pulmonary disease (COPD), the advantage of a long-acting beta agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) over a LABA plus an inhaled corticosteroid (ICS) was observed in every subgroup in the FLAME trial evaluated, according to post hoc analyses presented at the annual congress of the European Respiratory Society.

“We thought that we might not see the difference in the COPD patients with more severe disease, but the advantage was consistent even among those who entered the trial on triple therapy,” reported Jadwiga A. Wedzicha, MD, professor of respiratory medicine at the National Heart and Lung Institute, Imperial College, London.

FLAME, the recently published study that compared LABA/LAMA to LABA/ICS, was planned as a noninferiority study with the underlying hypothesis that LABA/LAMA would perform as well as LABA/ICS for the primary outcome of annual rate of COPD exacerbations (N Engl J Med. 2016;374:2222-34). Instead, the 11% lower rate of exacerbations for LABA/LAMA proved statistically significant (P = .003).

Six post hoc FLAME analyses were presented at the 2016 ERS Congress to further explore this result. All supported the main result. In addition to evaluating those who entered the trial on a LABA/LAMA/ICS triple-therapy combination, the analyses covered a broad array of subgroups defined by age, smoking history, and COPD severity as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifications.

In FLAME, 3,362 COPD patients who had at least one exacerbation in the preceding year were randomized to the LABA indacaterol (110 mcg) plus the LAMA glycopyrronium (50 mcg) once daily or the combination of the LABA salmeterol (50 mcg) and the ICS fluticasone (500 mcg) twice daily. In addition to the relative advantage on the primary outcome of any exacerbation, the LABA/LAMA combination also significantly reduced the rate of moderate to severe exacerbations (P less than .001), and it extended the times to the first moderate to severe exacerbation (P less than .001) and the first severe exacerbation (P = .046), according to the published data.

In the post hoc analyses, the advantage of LABA/LAMA relative to LAMA/ICS was remarkably consistent. For example, in stratifications made for age (less than 55 years, 55 to less than 65 years, 65-75 years, and greater than or equal to 75 years) at least a numerical advantage of LABA/LAMA was seen in all age groups for prevention of any exacerbation, and the difference reached statistical significance for those in the age group 55 to greater than 65 years. For prevention of moderate to severe exacerbations, the treatments were found to be equivalent for individuals younger than 55 years, but LABA/LAMA was statistically superior for the other three age categories.

For ex-smokers, unlike current smokers, the numerical advantage of LABA/LAMA over LABA/ICS for reduction in the rate ratio of all exacerbations did not reach statistical significance, but the LABA/LAMA combination did provide a statistically significant advantage for both ex-smokers and current smokers for moderate to severe exacerbations.

For patients with two or more exacerbations in the year prior to enrollment in FLAME, the relative degree of protection was of magnitude similar to that of patients with only one exacerbation even though the relative advantage in those with multiple prior exacerbations did not reach statistical significance. However, the lack of significance was likely due to the relatively small number of patients in this subpopulation, according to Dr. Wedzicha.

Similarly, the LABA/LAMA combination was at least numerically superior to LABA/ICS for all exacerbations and for moderate to severe exacerbations across GOLD classifications with one exception. When compared for relative protection against moderate to severe exacerbations, there was a slight and nonsignificant disadvantage for LABA/LAMA, but, again, Dr. Wedzicha reported, “the number of patients in this subgroup was quite small.”

In another FLAME post hoc analysis, the odds ratio (OR) for exacerbations among the 1,893 patients (56.3%) who were on ICS at study entry was found to be almost identical to the OR among those who were not. Specifically, the ORs for all exacerbations and moderate to severe exacerbations were 0.88 (P = .008) and 0.86 (P = .018), respectively, for those previously treated with ICS and 0.88 (P = .021) and 0.78 (P = .002), respectively, for those who had not been treated with ICS.

The LABA/LAMA combination was also superior to LABA/ICS for improvements in quality of life, which was measured via the St. George’s Respiratory Questionnaire. With an improvement of at least four units on the St. George’s Respiratory Questionnaire defined as clinically meaningful, 49.5% of LABA/LAMA patients versus 43.8% of LABA/ICS patients (P less than .024) benefited on this measure.

Overall, the results from the FLAME post hoc analyses have demonstrated “remarkable consistency,” Dr. Wedzicha reported. Taken together, she said the data “imply that LABA/LAMA is the first choice of treatment for COPD patients at risk of exacerbation.”

LONDON – In chronic obstructive pulmonary disease (COPD), the advantage of a long-acting beta agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) over a LABA plus an inhaled corticosteroid (ICS) was observed in every subgroup in the FLAME trial evaluated, according to post hoc analyses presented at the annual congress of the European Respiratory Society.

“We thought that we might not see the difference in the COPD patients with more severe disease, but the advantage was consistent even among those who entered the trial on triple therapy,” reported Jadwiga A. Wedzicha, MD, professor of respiratory medicine at the National Heart and Lung Institute, Imperial College, London.

FLAME, the recently published study that compared LABA/LAMA to LABA/ICS, was planned as a noninferiority study with the underlying hypothesis that LABA/LAMA would perform as well as LABA/ICS for the primary outcome of annual rate of COPD exacerbations (N Engl J Med. 2016;374:2222-34). Instead, the 11% lower rate of exacerbations for LABA/LAMA proved statistically significant (P = .003).

Six post hoc FLAME analyses were presented at the 2016 ERS Congress to further explore this result. All supported the main result. In addition to evaluating those who entered the trial on a LABA/LAMA/ICS triple-therapy combination, the analyses covered a broad array of subgroups defined by age, smoking history, and COPD severity as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifications.

In FLAME, 3,362 COPD patients who had at least one exacerbation in the preceding year were randomized to the LABA indacaterol (110 mcg) plus the LAMA glycopyrronium (50 mcg) once daily or the combination of the LABA salmeterol (50 mcg) and the ICS fluticasone (500 mcg) twice daily. In addition to the relative advantage on the primary outcome of any exacerbation, the LABA/LAMA combination also significantly reduced the rate of moderate to severe exacerbations (P less than .001), and it extended the times to the first moderate to severe exacerbation (P less than .001) and the first severe exacerbation (P = .046), according to the published data.

In the post hoc analyses, the advantage of LABA/LAMA relative to LAMA/ICS was remarkably consistent. For example, in stratifications made for age (less than 55 years, 55 to less than 65 years, 65-75 years, and greater than or equal to 75 years) at least a numerical advantage of LABA/LAMA was seen in all age groups for prevention of any exacerbation, and the difference reached statistical significance for those in the age group 55 to greater than 65 years. For prevention of moderate to severe exacerbations, the treatments were found to be equivalent for individuals younger than 55 years, but LABA/LAMA was statistically superior for the other three age categories.

For ex-smokers, unlike current smokers, the numerical advantage of LABA/LAMA over LABA/ICS for reduction in the rate ratio of all exacerbations did not reach statistical significance, but the LABA/LAMA combination did provide a statistically significant advantage for both ex-smokers and current smokers for moderate to severe exacerbations.

For patients with two or more exacerbations in the year prior to enrollment in FLAME, the relative degree of protection was of magnitude similar to that of patients with only one exacerbation even though the relative advantage in those with multiple prior exacerbations did not reach statistical significance. However, the lack of significance was likely due to the relatively small number of patients in this subpopulation, according to Dr. Wedzicha.

Similarly, the LABA/LAMA combination was at least numerically superior to LABA/ICS for all exacerbations and for moderate to severe exacerbations across GOLD classifications with one exception. When compared for relative protection against moderate to severe exacerbations, there was a slight and nonsignificant disadvantage for LABA/LAMA, but, again, Dr. Wedzicha reported, “the number of patients in this subgroup was quite small.”

In another FLAME post hoc analysis, the odds ratio (OR) for exacerbations among the 1,893 patients (56.3%) who were on ICS at study entry was found to be almost identical to the OR among those who were not. Specifically, the ORs for all exacerbations and moderate to severe exacerbations were 0.88 (P = .008) and 0.86 (P = .018), respectively, for those previously treated with ICS and 0.88 (P = .021) and 0.78 (P = .002), respectively, for those who had not been treated with ICS.

The LABA/LAMA combination was also superior to LABA/ICS for improvements in quality of life, which was measured via the St. George’s Respiratory Questionnaire. With an improvement of at least four units on the St. George’s Respiratory Questionnaire defined as clinically meaningful, 49.5% of LABA/LAMA patients versus 43.8% of LABA/ICS patients (P less than .024) benefited on this measure.

Overall, the results from the FLAME post hoc analyses have demonstrated “remarkable consistency,” Dr. Wedzicha reported. Taken together, she said the data “imply that LABA/LAMA is the first choice of treatment for COPD patients at risk of exacerbation.”

LONDON – Despite very promising activity in animal models of idiopathic pulmonary fibrosis (IPF), a monoclonal antibody targeted at an enzyme considered to be important to collagen cross-linking did not produce any improvement in progression-free survival (PFS), according to results of a multicenter study presented at the annual congress of the European Respiratory Society.

“This was such a negative study, there is no point in doing another,” reported Ganesh Raghu, MD, director of the Pulmonary Fibrosis Program at the University of Washington Medical Center, Seattle.

The focus of this study was simtuzumab, a monoclonal antibody targeted at lysyl oxidase like 2 (LOXL2), an enzyme which catalyzes a step in the formation of collagen crosslinks, which are thought to be important in fibrosis formation. Simtuzumab has been entered into clinical trials for treatment of several forms of fibrosis, including fibrosis in the liver.

“In animal models, simtuzumab has demonstrated efficacy in reducing fibrosis when administered prior to fibrosis formation or after the process has already begun,” Dr. Raghu explained. He said a large trial was initiated in IPF because the agent seemed so promising and because a large study was thought to be the best strategy to arrive at a definitive answer regarding safety and efficacy.

The drug was found safe but not effective. The independent data monitoring and safety committee terminated the trial early for futility.

In the study, 544 IPF patients were randomized to 125 mg simtuzumab or placebo administered subcutaneously once weekly. The primary endpoint was PFS, but there were a large number of secondary endpoints including hospitalization for progressive disease, change in 6-minute walk distance (6MWD), and overall survival.

For the endpoint of PFS, “there was absolutely no difference” between the groups receiving simtuzumab or placebo. When the patients were stratified for demonstrating above or below median expression of LOXL2, which was a prespecified analysis for the trial, there was still no difference between groups. Even when those in the top quarter percentile of LOXL2 expression were compared with those with less [expression of the enzyme], there was still “absolutely no difference.”

There was also no significant evidence of benefit for simtuzumab observed on key secondary endpoints, such as overall survival. When patients were stratified by baseline lung function as expressed by percentage of predicted forced expiratory volume in 1 second (FEV₁), there was no signal of benefit for those with severe, moderate, or mild impairment.

One criticism of this study raised after the presentation was that patients with 26% or greater of predicted FEV₁ were permitted into the study. It was suggested that such patients would be expected to already have a high degree of fibrosis and therefore would be less likely to benefit from an antifibrosis therapy. Dr. Raghu acknowledged this criticism, but he said it was important to include patients with advanced disease in order to generate an adequate event rate. Even with inclusion of patients with severe lung impairment, the mortality rate was less than 10%.

He concluded that there was no signal of benefit even among those with the greatest expression of the target.

“We absolutely need better markers for IPF,” Dr. Raghu maintained. While other members of the LOXL family of enzymes may still prove to be valuable markers of IPF risk and targets of therapy, these data appear to rule out a therapeutic role for blocking LOXL2.

Dr. Raghu is a consultant for Boehringer Ingelheim, Biogen, FibroGen, Gilead, Janssen, MedImmune, Promedior, Sanofi-Aventis, and Veracyte.

LONDON – Despite very promising activity in animal models of idiopathic pulmonary fibrosis (IPF), a monoclonal antibody targeted at an enzyme considered to be important to collagen cross-linking did not produce any improvement in progression-free survival (PFS), according to results of a multicenter study presented at the annual congress of the European Respiratory Society.

“This was such a negative study, there is no point in doing another,” reported Ganesh Raghu, MD, director of the Pulmonary Fibrosis Program at the University of Washington Medical Center, Seattle.

The focus of this study was simtuzumab, a monoclonal antibody targeted at lysyl oxidase like 2 (LOXL2), an enzyme which catalyzes a step in the formation of collagen crosslinks, which are thought to be important in fibrosis formation. Simtuzumab has been entered into clinical trials for treatment of several forms of fibrosis, including fibrosis in the liver.

“In animal models, simtuzumab has demonstrated efficacy in reducing fibrosis when administered prior to fibrosis formation or after the process has already begun,” Dr. Raghu explained. He said a large trial was initiated in IPF because the agent seemed so promising and because a large study was thought to be the best strategy to arrive at a definitive answer regarding safety and efficacy.

The drug was found safe but not effective. The independent data monitoring and safety committee terminated the trial early for futility.

In the study, 544 IPF patients were randomized to 125 mg simtuzumab or placebo administered subcutaneously once weekly. The primary endpoint was PFS, but there were a large number of secondary endpoints including hospitalization for progressive disease, change in 6-minute walk distance (6MWD), and overall survival.

For the endpoint of PFS, “there was absolutely no difference” between the groups receiving simtuzumab or placebo. When the patients were stratified for demonstrating above or below median expression of LOXL2, which was a prespecified analysis for the trial, there was still no difference between groups. Even when those in the top quarter percentile of LOXL2 expression were compared with those with less [expression of the enzyme], there was still “absolutely no difference.”

There was also no significant evidence of benefit for simtuzumab observed on key secondary endpoints, such as overall survival. When patients were stratified by baseline lung function as expressed by percentage of predicted forced expiratory volume in 1 second (FEV₁), there was no signal of benefit for those with severe, moderate, or mild impairment.

One criticism of this study raised after the presentation was that patients with 26% or greater of predicted FEV₁ were permitted into the study. It was suggested that such patients would be expected to already have a high degree of fibrosis and therefore would be less likely to benefit from an antifibrosis therapy. Dr. Raghu acknowledged this criticism, but he said it was important to include patients with advanced disease in order to generate an adequate event rate. Even with inclusion of patients with severe lung impairment, the mortality rate was less than 10%.

He concluded that there was no signal of benefit even among those with the greatest expression of the target.

“We absolutely need better markers for IPF,” Dr. Raghu maintained. While other members of the LOXL family of enzymes may still prove to be valuable markers of IPF risk and targets of therapy, these data appear to rule out a therapeutic role for blocking LOXL2.

Dr. Raghu is a consultant for Boehringer Ingelheim, Biogen, FibroGen, Gilead, Janssen, MedImmune, Promedior, Sanofi-Aventis, and Veracyte.

LONDON – Despite very promising activity in animal models of idiopathic pulmonary fibrosis (IPF), a monoclonal antibody targeted at an enzyme considered to be important to collagen cross-linking did not produce any improvement in progression-free survival (PFS), according to results of a multicenter study presented at the annual congress of the European Respiratory Society.

“This was such a negative study, there is no point in doing another,” reported Ganesh Raghu, MD, director of the Pulmonary Fibrosis Program at the University of Washington Medical Center, Seattle.

The focus of this study was simtuzumab, a monoclonal antibody targeted at lysyl oxidase like 2 (LOXL2), an enzyme which catalyzes a step in the formation of collagen crosslinks, which are thought to be important in fibrosis formation. Simtuzumab has been entered into clinical trials for treatment of several forms of fibrosis, including fibrosis in the liver.

“In animal models, simtuzumab has demonstrated efficacy in reducing fibrosis when administered prior to fibrosis formation or after the process has already begun,” Dr. Raghu explained. He said a large trial was initiated in IPF because the agent seemed so promising and because a large study was thought to be the best strategy to arrive at a definitive answer regarding safety and efficacy.

The drug was found safe but not effective. The independent data monitoring and safety committee terminated the trial early for futility.

In the study, 544 IPF patients were randomized to 125 mg simtuzumab or placebo administered subcutaneously once weekly. The primary endpoint was PFS, but there were a large number of secondary endpoints including hospitalization for progressive disease, change in 6-minute walk distance (6MWD), and overall survival.

For the endpoint of PFS, “there was absolutely no difference” between the groups receiving simtuzumab or placebo. When the patients were stratified for demonstrating above or below median expression of LOXL2, which was a prespecified analysis for the trial, there was still no difference between groups. Even when those in the top quarter percentile of LOXL2 expression were compared with those with less [expression of the enzyme], there was still “absolutely no difference.”

There was also no significant evidence of benefit for simtuzumab observed on key secondary endpoints, such as overall survival. When patients were stratified by baseline lung function as expressed by percentage of predicted forced expiratory volume in 1 second (FEV₁), there was no signal of benefit for those with severe, moderate, or mild impairment.

One criticism of this study raised after the presentation was that patients with 26% or greater of predicted FEV₁ were permitted into the study. It was suggested that such patients would be expected to already have a high degree of fibrosis and therefore would be less likely to benefit from an antifibrosis therapy. Dr. Raghu acknowledged this criticism, but he said it was important to include patients with advanced disease in order to generate an adequate event rate. Even with inclusion of patients with severe lung impairment, the mortality rate was less than 10%.

He concluded that there was no signal of benefit even among those with the greatest expression of the target.

“We absolutely need better markers for IPF,” Dr. Raghu maintained. While other members of the LOXL family of enzymes may still prove to be valuable markers of IPF risk and targets of therapy, these data appear to rule out a therapeutic role for blocking LOXL2.

Dr. Raghu is a consultant for Boehringer Ingelheim, Biogen, FibroGen, Gilead, Janssen, MedImmune, Promedior, Sanofi-Aventis, and Veracyte.