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Triple therapy for chronic obstructive pulmonary disease (COPD) achieved reductions in moderate to severe exacerbations when compared with two kinds of dual therapy, in a study published online in the New England Journal of Medicine.
The trial compared the outcomes of COPD patients using an inhaled therapy comprising a corticosteroid, a long-acting muscarinic antagonist (LAMA), and a long-acting beta2-agonist (LABA) with the outcomes of similar patients taking one of two other therapy combinations – a corticosteroid and a LABA, or a LABA and a LAMA. This trial – Informing the Pathway of COPD Treatment (IMPACT) – included 10,355 patients with symptomatic COPD in 37 countries, according to David A. Lipson, MD, and his colleagues (N Engl J Med. 2018 Apr 18. doi: 10.1056/NEJMoa1713901).
The study randomized patients to 52 weeks of either triple inhaled therapy involving a once-daily combination of 100 mcg fluticasone furoate (a corticosteroid), 62.5 mcg of the LAMA umeclidinium and 25 mcg of the LABA vilanterol; or dual inhaled therapy involving either 100 mcg fluticasone furoate plus 25 mcg of vilanterol, or 62.5 mcg of umeclidinium plus 25 mcg of vilanterol.
After 1 year, the rate of moderate to severe COPD exacerbations in the triple-therapy group was 0.91 per year, compared with 1.07 in the fluticasone furoate–vilanterol group and 1.21 in the vilanterol-umeclidinium group. This translated to a 15% reduction with triple therapy compared with fluticasone furoate–vilanterol and a 25% reduction compared with vilanterol-umeclidinium (P less than .001 for both).
When the analysis was limited to severe exacerbations alone, the difference was significant only between the triple therapy, which GSK is marketing as Trelegy Ellipta, and the vilanterol-umeclidinium dual therapy.
Dr. Lipson, of GSK and the University of Pennsylvania, and his coauthors noted that their finding of a greater benefit with the glucocorticoid-containing dual-therapy compared with the LABA-LAMA vilanterol-umeclidinium combination contradicted the findings of the earlier FLAME trial. This was likely due to differences in patient populations and design, as all patients in the FLAME trial had a 1-month run-in treatment with the bronchodilator tiotropium, the researchers explained.
“Therefore any patients who would require an inhaled glucocorticoid may have had an increase in exacerbations and a decrease in lung function during the run-in period and would have been forced to leave the trial,” they wrote.
Patients with higher eosinophil levels seemed to do even better with triple therapy. In those with eosinophil levels of 150 cells per microliter or above, the annual rate of moderate to severe exacerbations was 0.95 with triple therapy, 1.08 with fluticasone furoate–vilanterol, and 1.39 with vilanterol-umeclidinium.
Triple therapy also was associated with a significantly longer time to first event and greater improvements in quality of life, compared with the dual therapies.
Overall, the adverse event profile of triple therapy was similar to that of dual therapy. Contrasting that finding were differences in the incidences of physician-diagnosed pneumonia between the treatment groups. Physician-diagnosed pneumonia was 53% higher among patients who received fluticasone furoate – either in dual or triple therapy combinations. Eight percent of patients in the triple therapy group experienced pneumonia, compared with 7% of patients in the fluticasone furoate–vilanterol group and 5% in the vilanterol-umeclidinium group.
All-cause mortality was significantly lower in patients who received the inhaled glucocorticoid, although the authors said this finding was “fragile” and needed further investigation.
The rate of discontinuation or withdrawal from the trial was 6% for the triple therapy group, 8% for the fluticasone furoate–vilanterol group, and 9% for the vilanterol-umeclidinium group. The rates of serious adverse events in each group were 22%, 21%, and 23%, respectively.
At trial entry, 38% of patients were already receiving triple therapy and 29% were taking an inhaled glucocorticoid. The authors noted that any patients taking an inhaled glucocorticoid who were randomized to the vilanterol-umeclidinium group would have had to abruptly stop taking their inhaled glucocorticoids.
“It is unknown whether the abrupt discontinuation of inhaled glucocorticoids would have contributed to our finding of a lower rate of exacerbations in the inhaled glucocorticoid groups than in the LAMA-LABA group,” they wrote.
Fernando Martinez, MD, chief of the division of pulmonary and critical care medicine at New York–Presbyterian Hospital/Weill Cornell Medical Center, said the study advanced the understanding of COPD management by addressing some key evidence gaps, in a statement issued by GSK.
“By comparing various combinations of effective medications in the same device the study clarifies which type of patient gains greatest benefit from each class of medicine,” Dr Martinez said in the statement. “As many patients experience frequent exacerbations or ‘flare ups,’ which can often result in hospitalization, these data will be highly relevant to patients and clinicians as they consider the optimal treatment.”
The study was funded by GSK, which manufactures Trelegy Ellipta triple therapy for COPD. Eight authors were employees of GSK and two were on advisory boards for the company. Seven authors declared funding from a range of pharmaceutical companies including GSK. One author had no conflicts of interest to declare.
SOURCE: Lipson D et al. N Engl J Med. 2018 Apr 18. doi: 10.1056/NEJMoa1713901.
The data from the IMPACT study fills a gap in the evidence supporting a step-up from dual to triple inhaled therapy for COPD, which so far has been recommended only for patients with severe loss of lung function and those with frequent exacerbations despite maximum bronchodilator treatment. The study has the strengths of comparing the step-up to triple therapy with the GOLD guideline–recommended dual therapies and using the same dosages in the triple therapy as in the dual therapy
However, it is important to note that nearly 40% of patients enrolled in the trial were already being treated with triple therapy, 70% were receiving a glucocorticoid, and patients with a history of asthma were not excluded. This means patients assigned to the dual therapy without glucocorticoids would have had an abrupt cessation of their glucocorticoid therapy, which may explain a rapid surge in exacerbations in the first month and the lower rate of exacerbations in the dual-therapy group that did include glucocorticoids. The choice of patients for the study could potentially have artificially inflated the observed effectiveness of triple therapy over dual bronchodilator treatment.
As such, we suggest clinicians stick with the GOLD 2017 recommendations that escalation to triple therapy only occur after maximization of bronchodilator treatment.
Dr. Samy Suissa (PhD) is with the Center for Clinical Epidemiology at Lady Davis Institute–Jewish General Hospital, and the departments of epidemiology and biostatistics and medicine at McGill University, Montreal. Dr. Jeffrey M. Drazen is editor-in-chief of the New England Journal of Medicine. These comments are taken from an editorial (N Engl J Med. 2018 Apr 18. doi: 10.1056/NEJMe1716802 ). Dr. Suissa declared personal fees and grants from the pharmaceutical industry outside the submitted work.
The data from the IMPACT study fills a gap in the evidence supporting a step-up from dual to triple inhaled therapy for COPD, which so far has been recommended only for patients with severe loss of lung function and those with frequent exacerbations despite maximum bronchodilator treatment. The study has the strengths of comparing the step-up to triple therapy with the GOLD guideline–recommended dual therapies and using the same dosages in the triple therapy as in the dual therapy
However, it is important to note that nearly 40% of patients enrolled in the trial were already being treated with triple therapy, 70% were receiving a glucocorticoid, and patients with a history of asthma were not excluded. This means patients assigned to the dual therapy without glucocorticoids would have had an abrupt cessation of their glucocorticoid therapy, which may explain a rapid surge in exacerbations in the first month and the lower rate of exacerbations in the dual-therapy group that did include glucocorticoids. The choice of patients for the study could potentially have artificially inflated the observed effectiveness of triple therapy over dual bronchodilator treatment.
As such, we suggest clinicians stick with the GOLD 2017 recommendations that escalation to triple therapy only occur after maximization of bronchodilator treatment.
Dr. Samy Suissa (PhD) is with the Center for Clinical Epidemiology at Lady Davis Institute–Jewish General Hospital, and the departments of epidemiology and biostatistics and medicine at McGill University, Montreal. Dr. Jeffrey M. Drazen is editor-in-chief of the New England Journal of Medicine. These comments are taken from an editorial (N Engl J Med. 2018 Apr 18. doi: 10.1056/NEJMe1716802 ). Dr. Suissa declared personal fees and grants from the pharmaceutical industry outside the submitted work.
The data from the IMPACT study fills a gap in the evidence supporting a step-up from dual to triple inhaled therapy for COPD, which so far has been recommended only for patients with severe loss of lung function and those with frequent exacerbations despite maximum bronchodilator treatment. The study has the strengths of comparing the step-up to triple therapy with the GOLD guideline–recommended dual therapies and using the same dosages in the triple therapy as in the dual therapy
However, it is important to note that nearly 40% of patients enrolled in the trial were already being treated with triple therapy, 70% were receiving a glucocorticoid, and patients with a history of asthma were not excluded. This means patients assigned to the dual therapy without glucocorticoids would have had an abrupt cessation of their glucocorticoid therapy, which may explain a rapid surge in exacerbations in the first month and the lower rate of exacerbations in the dual-therapy group that did include glucocorticoids. The choice of patients for the study could potentially have artificially inflated the observed effectiveness of triple therapy over dual bronchodilator treatment.
As such, we suggest clinicians stick with the GOLD 2017 recommendations that escalation to triple therapy only occur after maximization of bronchodilator treatment.
Dr. Samy Suissa (PhD) is with the Center for Clinical Epidemiology at Lady Davis Institute–Jewish General Hospital, and the departments of epidemiology and biostatistics and medicine at McGill University, Montreal. Dr. Jeffrey M. Drazen is editor-in-chief of the New England Journal of Medicine. These comments are taken from an editorial (N Engl J Med. 2018 Apr 18. doi: 10.1056/NEJMe1716802 ). Dr. Suissa declared personal fees and grants from the pharmaceutical industry outside the submitted work.
Triple therapy for chronic obstructive pulmonary disease (COPD) achieved reductions in moderate to severe exacerbations when compared with two kinds of dual therapy, in a study published online in the New England Journal of Medicine.
The trial compared the outcomes of COPD patients using an inhaled therapy comprising a corticosteroid, a long-acting muscarinic antagonist (LAMA), and a long-acting beta2-agonist (LABA) with the outcomes of similar patients taking one of two other therapy combinations – a corticosteroid and a LABA, or a LABA and a LAMA. This trial – Informing the Pathway of COPD Treatment (IMPACT) – included 10,355 patients with symptomatic COPD in 37 countries, according to David A. Lipson, MD, and his colleagues (N Engl J Med. 2018 Apr 18. doi: 10.1056/NEJMoa1713901).
The study randomized patients to 52 weeks of either triple inhaled therapy involving a once-daily combination of 100 mcg fluticasone furoate (a corticosteroid), 62.5 mcg of the LAMA umeclidinium and 25 mcg of the LABA vilanterol; or dual inhaled therapy involving either 100 mcg fluticasone furoate plus 25 mcg of vilanterol, or 62.5 mcg of umeclidinium plus 25 mcg of vilanterol.
After 1 year, the rate of moderate to severe COPD exacerbations in the triple-therapy group was 0.91 per year, compared with 1.07 in the fluticasone furoate–vilanterol group and 1.21 in the vilanterol-umeclidinium group. This translated to a 15% reduction with triple therapy compared with fluticasone furoate–vilanterol and a 25% reduction compared with vilanterol-umeclidinium (P less than .001 for both).
When the analysis was limited to severe exacerbations alone, the difference was significant only between the triple therapy, which GSK is marketing as Trelegy Ellipta, and the vilanterol-umeclidinium dual therapy.
Dr. Lipson, of GSK and the University of Pennsylvania, and his coauthors noted that their finding of a greater benefit with the glucocorticoid-containing dual-therapy compared with the LABA-LAMA vilanterol-umeclidinium combination contradicted the findings of the earlier FLAME trial. This was likely due to differences in patient populations and design, as all patients in the FLAME trial had a 1-month run-in treatment with the bronchodilator tiotropium, the researchers explained.
“Therefore any patients who would require an inhaled glucocorticoid may have had an increase in exacerbations and a decrease in lung function during the run-in period and would have been forced to leave the trial,” they wrote.
Patients with higher eosinophil levels seemed to do even better with triple therapy. In those with eosinophil levels of 150 cells per microliter or above, the annual rate of moderate to severe exacerbations was 0.95 with triple therapy, 1.08 with fluticasone furoate–vilanterol, and 1.39 with vilanterol-umeclidinium.
Triple therapy also was associated with a significantly longer time to first event and greater improvements in quality of life, compared with the dual therapies.
Overall, the adverse event profile of triple therapy was similar to that of dual therapy. Contrasting that finding were differences in the incidences of physician-diagnosed pneumonia between the treatment groups. Physician-diagnosed pneumonia was 53% higher among patients who received fluticasone furoate – either in dual or triple therapy combinations. Eight percent of patients in the triple therapy group experienced pneumonia, compared with 7% of patients in the fluticasone furoate–vilanterol group and 5% in the vilanterol-umeclidinium group.
All-cause mortality was significantly lower in patients who received the inhaled glucocorticoid, although the authors said this finding was “fragile” and needed further investigation.
The rate of discontinuation or withdrawal from the trial was 6% for the triple therapy group, 8% for the fluticasone furoate–vilanterol group, and 9% for the vilanterol-umeclidinium group. The rates of serious adverse events in each group were 22%, 21%, and 23%, respectively.
At trial entry, 38% of patients were already receiving triple therapy and 29% were taking an inhaled glucocorticoid. The authors noted that any patients taking an inhaled glucocorticoid who were randomized to the vilanterol-umeclidinium group would have had to abruptly stop taking their inhaled glucocorticoids.
“It is unknown whether the abrupt discontinuation of inhaled glucocorticoids would have contributed to our finding of a lower rate of exacerbations in the inhaled glucocorticoid groups than in the LAMA-LABA group,” they wrote.
Fernando Martinez, MD, chief of the division of pulmonary and critical care medicine at New York–Presbyterian Hospital/Weill Cornell Medical Center, said the study advanced the understanding of COPD management by addressing some key evidence gaps, in a statement issued by GSK.
“By comparing various combinations of effective medications in the same device the study clarifies which type of patient gains greatest benefit from each class of medicine,” Dr Martinez said in the statement. “As many patients experience frequent exacerbations or ‘flare ups,’ which can often result in hospitalization, these data will be highly relevant to patients and clinicians as they consider the optimal treatment.”
The study was funded by GSK, which manufactures Trelegy Ellipta triple therapy for COPD. Eight authors were employees of GSK and two were on advisory boards for the company. Seven authors declared funding from a range of pharmaceutical companies including GSK. One author had no conflicts of interest to declare.
SOURCE: Lipson D et al. N Engl J Med. 2018 Apr 18. doi: 10.1056/NEJMoa1713901.
Triple therapy for chronic obstructive pulmonary disease (COPD) achieved reductions in moderate to severe exacerbations when compared with two kinds of dual therapy, in a study published online in the New England Journal of Medicine.
The trial compared the outcomes of COPD patients using an inhaled therapy comprising a corticosteroid, a long-acting muscarinic antagonist (LAMA), and a long-acting beta2-agonist (LABA) with the outcomes of similar patients taking one of two other therapy combinations – a corticosteroid and a LABA, or a LABA and a LAMA. This trial – Informing the Pathway of COPD Treatment (IMPACT) – included 10,355 patients with symptomatic COPD in 37 countries, according to David A. Lipson, MD, and his colleagues (N Engl J Med. 2018 Apr 18. doi: 10.1056/NEJMoa1713901).
The study randomized patients to 52 weeks of either triple inhaled therapy involving a once-daily combination of 100 mcg fluticasone furoate (a corticosteroid), 62.5 mcg of the LAMA umeclidinium and 25 mcg of the LABA vilanterol; or dual inhaled therapy involving either 100 mcg fluticasone furoate plus 25 mcg of vilanterol, or 62.5 mcg of umeclidinium plus 25 mcg of vilanterol.
After 1 year, the rate of moderate to severe COPD exacerbations in the triple-therapy group was 0.91 per year, compared with 1.07 in the fluticasone furoate–vilanterol group and 1.21 in the vilanterol-umeclidinium group. This translated to a 15% reduction with triple therapy compared with fluticasone furoate–vilanterol and a 25% reduction compared with vilanterol-umeclidinium (P less than .001 for both).
When the analysis was limited to severe exacerbations alone, the difference was significant only between the triple therapy, which GSK is marketing as Trelegy Ellipta, and the vilanterol-umeclidinium dual therapy.
Dr. Lipson, of GSK and the University of Pennsylvania, and his coauthors noted that their finding of a greater benefit with the glucocorticoid-containing dual-therapy compared with the LABA-LAMA vilanterol-umeclidinium combination contradicted the findings of the earlier FLAME trial. This was likely due to differences in patient populations and design, as all patients in the FLAME trial had a 1-month run-in treatment with the bronchodilator tiotropium, the researchers explained.
“Therefore any patients who would require an inhaled glucocorticoid may have had an increase in exacerbations and a decrease in lung function during the run-in period and would have been forced to leave the trial,” they wrote.
Patients with higher eosinophil levels seemed to do even better with triple therapy. In those with eosinophil levels of 150 cells per microliter or above, the annual rate of moderate to severe exacerbations was 0.95 with triple therapy, 1.08 with fluticasone furoate–vilanterol, and 1.39 with vilanterol-umeclidinium.
Triple therapy also was associated with a significantly longer time to first event and greater improvements in quality of life, compared with the dual therapies.
Overall, the adverse event profile of triple therapy was similar to that of dual therapy. Contrasting that finding were differences in the incidences of physician-diagnosed pneumonia between the treatment groups. Physician-diagnosed pneumonia was 53% higher among patients who received fluticasone furoate – either in dual or triple therapy combinations. Eight percent of patients in the triple therapy group experienced pneumonia, compared with 7% of patients in the fluticasone furoate–vilanterol group and 5% in the vilanterol-umeclidinium group.
All-cause mortality was significantly lower in patients who received the inhaled glucocorticoid, although the authors said this finding was “fragile” and needed further investigation.
The rate of discontinuation or withdrawal from the trial was 6% for the triple therapy group, 8% for the fluticasone furoate–vilanterol group, and 9% for the vilanterol-umeclidinium group. The rates of serious adverse events in each group were 22%, 21%, and 23%, respectively.
At trial entry, 38% of patients were already receiving triple therapy and 29% were taking an inhaled glucocorticoid. The authors noted that any patients taking an inhaled glucocorticoid who were randomized to the vilanterol-umeclidinium group would have had to abruptly stop taking their inhaled glucocorticoids.
“It is unknown whether the abrupt discontinuation of inhaled glucocorticoids would have contributed to our finding of a lower rate of exacerbations in the inhaled glucocorticoid groups than in the LAMA-LABA group,” they wrote.
Fernando Martinez, MD, chief of the division of pulmonary and critical care medicine at New York–Presbyterian Hospital/Weill Cornell Medical Center, said the study advanced the understanding of COPD management by addressing some key evidence gaps, in a statement issued by GSK.
“By comparing various combinations of effective medications in the same device the study clarifies which type of patient gains greatest benefit from each class of medicine,” Dr Martinez said in the statement. “As many patients experience frequent exacerbations or ‘flare ups,’ which can often result in hospitalization, these data will be highly relevant to patients and clinicians as they consider the optimal treatment.”
The study was funded by GSK, which manufactures Trelegy Ellipta triple therapy for COPD. Eight authors were employees of GSK and two were on advisory boards for the company. Seven authors declared funding from a range of pharmaceutical companies including GSK. One author had no conflicts of interest to declare.
SOURCE: Lipson D et al. N Engl J Med. 2018 Apr 18. doi: 10.1056/NEJMoa1713901.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Triple COPD therapy shows fewer exacerbations than does dual therapy.
Major finding: Triple COPD therapy achieves a 15%-25% greater reduction in exacerbations compared with dual therapy.
Study details: Randomized controlled trial of 10,355 patients with symptomatic COPD.
Disclosures: The study was funded by GlaxoSmithKline, which manufactures Trelegy Ellipta triple therapy for COPD. Eight authors were employees of GlaxoSmithKline and two were on advisory boards for the company. Seven authors declared funding from a range of pharmaceutical companies including GlaxoSmithKline. One author had no conflicts of interest to declare.
Source: Lipson D et al. N Engl J Med. 2018 Apr 18. doi: 10.1056/NEJMoa1713901.