Dual bronchodilator combination shines in patients with high-risk COPD

SAN FRANCISCO – It may be time to revise guidelines when it comes to initial treatment of chronic obstructive pulmonary disease (COPD) complicated by exacerbations, based on data from a phase III trial reported at an international conference of the American Thoracic Society.

The trial, known as FLAME, undertook a head-to-head comparison of two inhaled drug combinations among more than 3,300 patients from 43 countries. Patients were randomized to once-daily indacaterol (a long-acting beta-agonist, or LABA, bronchodilator) and glycopyrronium (a long-acting muscarinic antagonist, or LAMA, bronchodilator), or to twice-daily salmeterol, also a LABA bronchodilator, and the inhaled glucocorticoid fluticasone.

After a year, the annual rate of exacerbations was 11% lower with indacaterol-glycopyrronium than with salmeterol-fluticasone, according to results reported in a press conference and simultaneously published (N Engl J Med. 2016 May 15. doi: 10.1056/NEJMoa1516385). The difference not only met the trial’s primary endpoint of noninferiority, but also established superiority.

The dual bronchodilator combination was also superior to salmeterol-fluticasone when it came to other outcomes, such as respiratory-related health status and rescue medication use, and it had a good safety profile.

“I think we can say that... a dual bronchodilator is the first-choice combination that can be used in patients with COPD,” commented lead author Dr. Jadwiga A. Wedzicha, a professor of respiratory medicine at the National Heart and Lung Institute, Imperial College London.

“This has a lot of implications. We are going to have to rewrite the guidelines and change our algorithms,” she said, noting that they currently recommend a LABA with an inhaled corticosteroid (the latter of which has adverse effects, especially in an aging population) or single-agent LAMA. “I’m pretty convinced by the data. We’ve got basically four LABA-LAMAs out there; we need to see other studies and look at different patient populations. But I think the data is pretty persuasive, so that we can now change our algorithms.”

Several ongoing studies are looking at triple therapy of a LABA-LAMA plus an inhaled corticosteroid, which may be useful in patients who continue to have exacerbations on dual bronchodilator therapy, according to Dr. Wedzicha. “I think we’ll move to the triple [therapy], because breathlessness is a problem,” she predicted, noting that bronchodilators address that symptom well. “As you get more severe, you are going to get short of breath. So I think the LABA-LAMA will stay and the inhaled corticosteroid will be added on top. That’s what I think COPD treatment will look like.”

Press conference moderator Dr. David Mannino, professor & chair (Preventive Medicine & Environmental Health) at the University of Kentucky College of Public Health in Lexington, praised the research but disagreed about its implications. “I think one very good study is just that – one very good study. Is that enough to change guidelines? I don’t think so,” he said in an interview. “I’d like to see this replicated, because in the U.S., for example, this medication isn’t even available. And if I write [a prescription] for one LABA-LAMA, what a patient actually gets may be dictated by their insurance and coverage and other things.”

“So I would like to see this done with other LABA-LAMAs, and see other head-to-head trials,” he elaborated. “And there is a great deal of boldness and risk on the part of drug companies to do head-to-head trials because they might not get a win. They lucked out in this one. You could do the same trial with products from different companies and not get the same results. And then you are left wondering what was wrong, was it patient characteristics or other things.”

The 3,362 patients studied in FLAME had disabling, symptomatic COPD and had experienced at least one exacerbation in the past year. They were randomized evenly to once-daily indacaterol-glycopyrronium (marketed outside the United States) or twice-daily salmeterol-fluticasone.

Results showed that the annual rate of any exacerbation was significantly lower with indacaterol-glycopyrronium than with salmeterol-fluticasone in the per protocol population (3.59 vs. 4.03; rate ratio, 0.89), with similar findings in the intent-to-treat population. Additionally, in a preplanned analysis, the findings were consistent regardless of patients’ blood levels of eosinophils, a possible marker of steroid sensitivity.

Indacaterol-glycopyrronium was also associated with a longer time to first exacerbation (71 vs. 51 days; hazard ratio, 0.84) and a lower annual rate of moderate or severe exacerbations (0.98 vs. 1.19; rate ratio, 0.83).

There was no difference between groups in the risk of death, but the study lasted only a year and was not powered for that endpoint, Dr. Wedzicha pointed out. “We are seeing less deaths in patients generally in COPD because we are monitoring them very carefully,” she added.

Indacaterol-glycopyrronium was also superior to salmeterol-fluticasone when it came to improvements in health status (assessed with the St. George’s Respiratory Questionnaire), use of rescue medication, and lung function.

The adverse event profiles of both drug combinations were essentially as expected, Dr. Wedzicha reported. Pneumonia was less common with indacaterol-glycopyrronium (3.2% vs. 4.8%).

The indacaterol-glycopyrronium formulation available in the United States, which contains lower doses of the drugs and is used twice-daily, would likely net results similar to those seen in the trial, she speculated. However, once-daily treatment is generally associated with better compliance.

The inflammatory component of COPD still needs attention, according to Dr. Wedzicha. “There is no good evidence that a LABA-LAMA is doing anything to the underlying airway inflammation ... I think a major unmet need now is novel anti-inflammatory agents,” she said.

Dr. Wedzicha disclosed that she received nonfinancial support from Novartis during the conduct of the study; grant support and personal fees from Johnson and Johnson and Vifor Pharma; grant support, personal fees, and nonfinancial support from GlaxoSmithKline, and Takeda; personal fees from Pfizer, Bayer, Chiesi, and Napp; and personal fees and nonfinancial support from Novartis, AstraZeneca, and Boehringer Ingelheim outside the trial. The trial was sponsored by Novartis.

SAN FRANCISCO – It may be time to revise guidelines when it comes to initial treatment of chronic obstructive pulmonary disease (COPD) complicated by exacerbations, based on data from a phase III trial reported at an international conference of the American Thoracic Society.

The trial, known as FLAME, undertook a head-to-head comparison of two inhaled drug combinations among more than 3,300 patients from 43 countries. Patients were randomized to once-daily indacaterol (a long-acting beta-agonist, or LABA, bronchodilator) and glycopyrronium (a long-acting muscarinic antagonist, or LAMA, bronchodilator), or to twice-daily salmeterol, also a LABA bronchodilator, and the inhaled glucocorticoid fluticasone.

After a year, the annual rate of exacerbations was 11% lower with indacaterol-glycopyrronium than with salmeterol-fluticasone, according to results reported in a press conference and simultaneously published (N Engl J Med. 2016 May 15. doi: 10.1056/NEJMoa1516385). The difference not only met the trial’s primary endpoint of noninferiority, but also established superiority.

The dual bronchodilator combination was also superior to salmeterol-fluticasone when it came to other outcomes, such as respiratory-related health status and rescue medication use, and it had a good safety profile.

“I think we can say that... a dual bronchodilator is the first-choice combination that can be used in patients with COPD,” commented lead author Dr. Jadwiga A. Wedzicha, a professor of respiratory medicine at the National Heart and Lung Institute, Imperial College London.

“This has a lot of implications. We are going to have to rewrite the guidelines and change our algorithms,” she said, noting that they currently recommend a LABA with an inhaled corticosteroid (the latter of which has adverse effects, especially in an aging population) or single-agent LAMA. “I’m pretty convinced by the data. We’ve got basically four LABA-LAMAs out there; we need to see other studies and look at different patient populations. But I think the data is pretty persuasive, so that we can now change our algorithms.”

Several ongoing studies are looking at triple therapy of a LABA-LAMA plus an inhaled corticosteroid, which may be useful in patients who continue to have exacerbations on dual bronchodilator therapy, according to Dr. Wedzicha. “I think we’ll move to the triple [therapy], because breathlessness is a problem,” she predicted, noting that bronchodilators address that symptom well. “As you get more severe, you are going to get short of breath. So I think the LABA-LAMA will stay and the inhaled corticosteroid will be added on top. That’s what I think COPD treatment will look like.”

Press conference moderator Dr. David Mannino, professor & chair (Preventive Medicine & Environmental Health) at the University of Kentucky College of Public Health in Lexington, praised the research but disagreed about its implications. “I think one very good study is just that – one very good study. Is that enough to change guidelines? I don’t think so,” he said in an interview. “I’d like to see this replicated, because in the U.S., for example, this medication isn’t even available. And if I write [a prescription] for one LABA-LAMA, what a patient actually gets may be dictated by their insurance and coverage and other things.”

“So I would like to see this done with other LABA-LAMAs, and see other head-to-head trials,” he elaborated. “And there is a great deal of boldness and risk on the part of drug companies to do head-to-head trials because they might not get a win. They lucked out in this one. You could do the same trial with products from different companies and not get the same results. And then you are left wondering what was wrong, was it patient characteristics or other things.”

The 3,362 patients studied in FLAME had disabling, symptomatic COPD and had experienced at least one exacerbation in the past year. They were randomized evenly to once-daily indacaterol-glycopyrronium (marketed outside the United States) or twice-daily salmeterol-fluticasone.

Results showed that the annual rate of any exacerbation was significantly lower with indacaterol-glycopyrronium than with salmeterol-fluticasone in the per protocol population (3.59 vs. 4.03; rate ratio, 0.89), with similar findings in the intent-to-treat population. Additionally, in a preplanned analysis, the findings were consistent regardless of patients’ blood levels of eosinophils, a possible marker of steroid sensitivity.

Indacaterol-glycopyrronium was also associated with a longer time to first exacerbation (71 vs. 51 days; hazard ratio, 0.84) and a lower annual rate of moderate or severe exacerbations (0.98 vs. 1.19; rate ratio, 0.83).

There was no difference between groups in the risk of death, but the study lasted only a year and was not powered for that endpoint, Dr. Wedzicha pointed out. “We are seeing less deaths in patients generally in COPD because we are monitoring them very carefully,” she added.

Indacaterol-glycopyrronium was also superior to salmeterol-fluticasone when it came to improvements in health status (assessed with the St. George’s Respiratory Questionnaire), use of rescue medication, and lung function.

The adverse event profiles of both drug combinations were essentially as expected, Dr. Wedzicha reported. Pneumonia was less common with indacaterol-glycopyrronium (3.2% vs. 4.8%).

The indacaterol-glycopyrronium formulation available in the United States, which contains lower doses of the drugs and is used twice-daily, would likely net results similar to those seen in the trial, she speculated. However, once-daily treatment is generally associated with better compliance.

The inflammatory component of COPD still needs attention, according to Dr. Wedzicha. “There is no good evidence that a LABA-LAMA is doing anything to the underlying airway inflammation ... I think a major unmet need now is novel anti-inflammatory agents,” she said.

Dr. Wedzicha disclosed that she received nonfinancial support from Novartis during the conduct of the study; grant support and personal fees from Johnson and Johnson and Vifor Pharma; grant support, personal fees, and nonfinancial support from GlaxoSmithKline, and Takeda; personal fees from Pfizer, Bayer, Chiesi, and Napp; and personal fees and nonfinancial support from Novartis, AstraZeneca, and Boehringer Ingelheim outside the trial. The trial was sponsored by Novartis.

SAN FRANCISCO – It may be time to revise guidelines when it comes to initial treatment of chronic obstructive pulmonary disease (COPD) complicated by exacerbations, based on data from a phase III trial reported at an international conference of the American Thoracic Society.

The trial, known as FLAME, undertook a head-to-head comparison of two inhaled drug combinations among more than 3,300 patients from 43 countries. Patients were randomized to once-daily indacaterol (a long-acting beta-agonist, or LABA, bronchodilator) and glycopyrronium (a long-acting muscarinic antagonist, or LAMA, bronchodilator), or to twice-daily salmeterol, also a LABA bronchodilator, and the inhaled glucocorticoid fluticasone.

After a year, the annual rate of exacerbations was 11% lower with indacaterol-glycopyrronium than with salmeterol-fluticasone, according to results reported in a press conference and simultaneously published (N Engl J Med. 2016 May 15. doi: 10.1056/NEJMoa1516385). The difference not only met the trial’s primary endpoint of noninferiority, but also established superiority.

The dual bronchodilator combination was also superior to salmeterol-fluticasone when it came to other outcomes, such as respiratory-related health status and rescue medication use, and it had a good safety profile.

“I think we can say that... a dual bronchodilator is the first-choice combination that can be used in patients with COPD,” commented lead author Dr. Jadwiga A. Wedzicha, a professor of respiratory medicine at the National Heart and Lung Institute, Imperial College London.

“This has a lot of implications. We are going to have to rewrite the guidelines and change our algorithms,” she said, noting that they currently recommend a LABA with an inhaled corticosteroid (the latter of which has adverse effects, especially in an aging population) or single-agent LAMA. “I’m pretty convinced by the data. We’ve got basically four LABA-LAMAs out there; we need to see other studies and look at different patient populations. But I think the data is pretty persuasive, so that we can now change our algorithms.”

Several ongoing studies are looking at triple therapy of a LABA-LAMA plus an inhaled corticosteroid, which may be useful in patients who continue to have exacerbations on dual bronchodilator therapy, according to Dr. Wedzicha. “I think we’ll move to the triple [therapy], because breathlessness is a problem,” she predicted, noting that bronchodilators address that symptom well. “As you get more severe, you are going to get short of breath. So I think the LABA-LAMA will stay and the inhaled corticosteroid will be added on top. That’s what I think COPD treatment will look like.”

Press conference moderator Dr. David Mannino, professor & chair (Preventive Medicine & Environmental Health) at the University of Kentucky College of Public Health in Lexington, praised the research but disagreed about its implications. “I think one very good study is just that – one very good study. Is that enough to change guidelines? I don’t think so,” he said in an interview. “I’d like to see this replicated, because in the U.S., for example, this medication isn’t even available. And if I write [a prescription] for one LABA-LAMA, what a patient actually gets may be dictated by their insurance and coverage and other things.”

“So I would like to see this done with other LABA-LAMAs, and see other head-to-head trials,” he elaborated. “And there is a great deal of boldness and risk on the part of drug companies to do head-to-head trials because they might not get a win. They lucked out in this one. You could do the same trial with products from different companies and not get the same results. And then you are left wondering what was wrong, was it patient characteristics or other things.”

The 3,362 patients studied in FLAME had disabling, symptomatic COPD and had experienced at least one exacerbation in the past year. They were randomized evenly to once-daily indacaterol-glycopyrronium (marketed outside the United States) or twice-daily salmeterol-fluticasone.

Results showed that the annual rate of any exacerbation was significantly lower with indacaterol-glycopyrronium than with salmeterol-fluticasone in the per protocol population (3.59 vs. 4.03; rate ratio, 0.89), with similar findings in the intent-to-treat population. Additionally, in a preplanned analysis, the findings were consistent regardless of patients’ blood levels of eosinophils, a possible marker of steroid sensitivity.

Indacaterol-glycopyrronium was also associated with a longer time to first exacerbation (71 vs. 51 days; hazard ratio, 0.84) and a lower annual rate of moderate or severe exacerbations (0.98 vs. 1.19; rate ratio, 0.83).

There was no difference between groups in the risk of death, but the study lasted only a year and was not powered for that endpoint, Dr. Wedzicha pointed out. “We are seeing less deaths in patients generally in COPD because we are monitoring them very carefully,” she added.

Indacaterol-glycopyrronium was also superior to salmeterol-fluticasone when it came to improvements in health status (assessed with the St. George’s Respiratory Questionnaire), use of rescue medication, and lung function.

The adverse event profiles of both drug combinations were essentially as expected, Dr. Wedzicha reported. Pneumonia was less common with indacaterol-glycopyrronium (3.2% vs. 4.8%).

The indacaterol-glycopyrronium formulation available in the United States, which contains lower doses of the drugs and is used twice-daily, would likely net results similar to those seen in the trial, she speculated. However, once-daily treatment is generally associated with better compliance.

The inflammatory component of COPD still needs attention, according to Dr. Wedzicha. “There is no good evidence that a LABA-LAMA is doing anything to the underlying airway inflammation ... I think a major unmet need now is novel anti-inflammatory agents,” she said.

Dr. Wedzicha disclosed that she received nonfinancial support from Novartis during the conduct of the study; grant support and personal fees from Johnson and Johnson and Vifor Pharma; grant support, personal fees, and nonfinancial support from GlaxoSmithKline, and Takeda; personal fees from Pfizer, Bayer, Chiesi, and Napp; and personal fees and nonfinancial support from Novartis, AstraZeneca, and Boehringer Ingelheim outside the trial. The trial was sponsored by Novartis.